Bridged piperidine derivatives as melanocortin receptor agonists

ABSTRACT

Certain novel bridged piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US02/22258, filed Jul. 12, 2002, whichclaims priority under 35 U.S.C. §119 from U.S. Provisional ApplicationNo. 60/306,359, Jul. 18, 2001.

FIELD OF THE INVENTION

The present invention relates to bridged piperidine derivatives, theirsynthesis, and their use as melanocortin receptor (MC-R) agonists. Moreparticularly, the compounds of the present invention are selectiveagonists of the melanocortin-4 receptor (MC-4R) and are thereby usefulfor the treatment of disorders responsive to the activation of MC-4R,such as obesity, diabetes, male sexual dysfunction, and female sexualdysfunction.

BACKGROUND OF THE INVENTION

Pro-opiomelanocortin (POMC) derived peptides are known to affect foodintake. Several lines of evidence support the notion that the G-proteincoupled receptors (GPCRs) of the melanocortin receptor (MC-R) family,several of which are expressed in the brain, are the targets of POMCderived peptides involved in the control of food intake and metabolism.A specific single MC-R that may be targeted for the control of obesityhas not yet been identified, although evidence has been presented thatMC-4R signalling is important in mediating feed behavior (S. Q. Giraudoet al., “Feeding effects of hypothalamic injection of melanocortin-4receptor ligands,” Brain Research, 80: 302–306 (1998)).

Evidence for the involvement of MC-R's in obesity includes: i) theagouti (A^(vy)) mouse which ectopically expresses an antagonist of theMC-1R, MC-3R and -4R is obese, indicating that blocking the action ofthese three MC-R's can lead to hyperphagia and metabolic disorders; ii)MC-4R knockout mice (D. Huszar et al., Cell, 88: 131–141 (1997))recapitulate the phenotype of the agouti mouse and these mice are obese;iii) the cyclic heptapeptide MT-II (a non-selective MC-1R, -3R, -4R, and-5R agonist) injected intracerebroventricularly (ICV) in rodents,reduces food intake in several animal feeding models (NPY, ob/ob,agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist;MC-1R and -5R agonist) reverses this effect and can induce hyperphagia;iv) chronic intraperitoneal treatment of Zucker fatty rats with anα-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R,-4R, and -5R and to attenuate food intake and body weight gain over a12-week period (I. Corcos et al., “HP228 is a potent agonist ofmelanocortin receptor-4 and significantly attenuates obesity anddiabetes in Zucker fatty rats,” Society for Neuroscience Abstracts, 23:673 (1997)).

Five distinct MC-R's have thus far been identified, and these areexpressed in different tissues. MC-1R was initially characterized bydominant gain of function mutations at the Extension locus, affectingcoat color by controlling phaeomelanin to eumelanin conversion throughcontrol of tyrosinase. MC-1R is mainly expressed in melanocytes. MC-2Ris expressed in the adrenal gland and represents the ACTH receptor.MC-3R is expressed in the brain, gut, and placenta and may be involvedin the control of food intake and thermogenesis. MC-4R is uniquelyexpressed in the brain, and its inactivation was shown to cause obesity(A. Kask, et al., “Selective antagonist for the melanocortin-4 receptor(HS014) increases food intake in free-feeding rats,” Biochem. Biophys.Res. Commun., 245: 90–93 (1998)). MC-5R is expressed in many tissues,including white fat, placenta and exocrine glands. A low level ofexpression is also observed in the brain. MC-5R knockout mice revealreduced sebaceous gland lipid production (Chen et al., Cell, 91: 789–798(1997)).

Erectile dysfunction denotes the medical condition of inability toachieve penile erection sufficient for successful sexual intercourse.The term “impotence” is oftentimes employed to describe this prevalentcondition. Approximately 140 million men worldwide, and, according to aNational Institutes of Health study, about 30 million American mensuffer from impotency or erectile dysfunction. It has been estimatedthat the latter number could rise to 47 million men by the year 2000.Erectile dysfunction can arise from either organic or psychogeniccauses, with about 20% of such cases being purely psychogenic in origin.Erectile dysfunction increases from 40% at age 40, to 67% at age 75,with over 75% occurring in men over the age of 50. In spite of thefrequent occurrence of this condition, only a small number of patientshave received treatment because existing treatment alternatives, such asinjection therapies, penile prosthesis implantation, and vacuum pumps,have been uniformly disagreeable [for a discussion, see “ABC of sexualhealth—erectile dysfunction,” Brit. Med. J. 318: 387–390 (1999)]. Onlymore recently have more viable treatment modalities become available, inparticular orally active agents, such as sildenafil citrate, marketed byPfizer under the brand name of Viagra®. (See “Emerging pharmacologicaltherapies for erectile dysfunction,” Exp. Opin. Ther. Patents 9:1689–1696 (1999)). Sildenafil is a selective inhibitor of type Vphosphodiesterase (PDE-V), a cyclic-GMP-specific phosphodiesteraseisozyme [see R. B. Moreland et al., “Sildenafil: A Novel Inhibitor ofPhosphodiesterase Type 5 in Human Corpus Cavernosum Smooth MuscleCells,” Life Sci., 62: 309–318 (1998)]. Prior to the introduction ofViagra on the market, less than 10% of patients suffering from erectiledysfunction received treatment. Sildenafil is also being evaluated inthe clinic for the treatment of female sexual dysfunction.

The regulatory approval of Viagra® for the oral treatment of erectiledysfunction has invigorated efforts to discover even more effectivemethods to treat erectile dysfunction. Several additional selectivePDE-V inhibitors are in clinical trials. UK-114542 is a sildenafilbackup from Pfizer with supposedly improved properties. IC-351 (ICOSCorp.) is claimed to have greater selectivity for PDE-V over PDE-VI thansildenafil. Other PDE-V inhibitors include M-54033 and M-54018 fromMochida Pharmaceutical Co. and E-4010 from Eisai Co., Ltd.

Other pharmacological approaches to the treatment of erectiledysfunction have been described [see, e.g., “Latest Findings on theDiagnosis and Treatment of Erectile Dysfunction,” Drug News &Perspectives, 9: 572–575 (1996); “Oral Pharmacotherapy in ErectileDysfunction,” Current Opinion in Urology, 7: 349–353 (1997)]. A productunder clinical development by Zonagen is an oral formulation of thealpha-adrenoceptor antagonist phentolamine mesylate under the brand nameof Vasomax®. Vasomax® is also being evaluated for the treatment offemale sexual dysfunction.

Drugs to treat erectile dysfunction act either peripherally orcentrally. They are also classified according to whether they “initiate”a sexual response or “facilitate” a sexual response to prior stimulation[for a discussion, see “A Therapeutic Taxonomy of Treatments forErectile Dysfunction: An Evolutionary Imperative,” Int. J. ImpotenceRes., 9: 115–121 (1997)]. While sildenafil and phentolamine actperipherally and are considered to be “enhancers” or “facilitators” ofthe sexual response to erotic stimulation, sildenafil appears to beefficacious in both mild organic and psychogenic erectile dysfunction.Sildenafil has an onset of action of 30–60 minutes after an oral dosewith the effect lasting about 4 hours, whereas phentolamine requires5–30 minutes for onset with a duration of 2 hours. Although sildenafilis effective in a majority of patients, it takes a relatively long timefor the compound to show the desired effects. The faster-actingphentolamine appears to be less effective and to have a shorter durationof action than sildenafil. Oral sildenafil is effective in about 70% ofmen who take it, whereas an adequate response with phentolamine isobserved in only 35–40% of patients. Both compounds require eroticstimulation for efficacy. Since sildenafil indirectly increases bloodflow in the systemic circulation by enhancing the smooth musclerelaxation effects of nitric oxide, it is contraindicated for patientswith unstable heart conditions or cardiovascular disease, in particularpatients taking nitrates, such as nitroglycerin, to treat angina. Otheradverse effects associated with the clinical use of sildenafil includeheadache, flushing, dyspepsia, and “abnormal vision,” the latter theresult of inhibition of the type VI phosphodiesterase isozyme (PDE-VI),a cyclic-GMP-specific phosphodiesterase that is concentrated in theretina. “Abnormal vision” is defined as a mild and transient “bluish”tinge to vision, but also an increased sensitivity to light or blurredvision.

Synthetic melanocortin receptor agonists (melanotropic peptides) havebeen found to initiate erections in men with psychogenic erectiledysfunction [See H. Wessells et al., “Synthetic Melanotropic PeptideInitiates Erections in Men With Psychogenic Erectile Dysfunction:Double-Blind, Placebo Controlled Crossover Study,” J. Urol., 160:389–393 (1998); Fifteenth American Peptide Symposium, Jun. 14–19, 1997(Nashville Tenn.)]. Activation of melanocortin receptors of the brainappears to cause normal stimulation of sexual arousal. In the abovestudy, the centrally acting α-melanocyte-stimulating hormone analog,melanotan-II (MT-II), exhibited a 75% response rate, similar to resultsobtained with apomorphine, when injected intramuscularly orsubcutaneously to males with psychogenic erectile dysfunction. MT-II isa synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH₂,which contains the 4–10 melanocortin receptor binding region common toα-MSH and adrenocorticotropin, but with a lactam bridge. It is anon-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., LifeSciences, Vol. 58, 1777–1784, 1996). MT-II (also referred to as PT-14)(Erectide®) is presently in clinical development by PalatinTechnologies, Inc. and TheraTech, Inc. as a non-penile subcutaneousinjection formulation. It is considered to be an “initiator” of thesexual response. The time to onset of erection with this drug isrelatively short (10–20 minutes) with a duration of action approximately2.5 hours. Adverse reactions observed with MT-II include nausea,flushing, loss of appetite, stretching, and yawning and may be theresult of activation of MC-1R, MC-2R, MC-3R, and/or MC-5R. MT-II must beadministered parenterally, such as by subcutaneous, intravenous, orintramuscular route, since it is not absorbed into the systemiccirculation when given by the oral route.

MT-II's erectogenic properties apparently are not limited to cases ofpsychogenic erectile dysfunction in that men with a variety of organicrisk factors developed penile erections upon subcutaneous injection ofthe compound; moreover, the level of sexual desire was significantlyhigher after MT-II administration than after placebo [see H. Wessells,“Effect of an Alpha-Melanocyte Stimulating Hormone Analog on PenileErection and Sexual Desire in Men with Organic Erectile Dysfunction,”Urology, 56: 641–646 (2000)].

Compositions of melanotropic peptides and methods for the treatment ofpsychogenic erectile dysfunction are disclosed in U.S. Pat. No.5,576,290, assigned to Competitive Technologies. Methods of stimulatingsexual response in females using melanotropic peptides have beendisclosed in U.S. Pat. No. 6,051,555.

Spiropiperidine and piperidine derivatives have been disclosed in WO99/64002 (16 Dec. 1999) and WO 00/74679 (14 Dec. 2000), respectively, asagonists of the melanocortin receptor(s) and thereby useful for thetreatment of diseases and disorders, such as obesity, diabetes, andsexual dysfunction, including erectile dysfunction and female sexualdysfunction.

Because of the unresolved deficiencies of the various pharmacologicalagents discussed above, there is a continuing need in the medical artsfor improved methods and compositions to treat individuals sufferingfrom psychogenic and/or organic sexual dysfunction. Such methods shouldhave wider applicability, enhanced convenience and ease of compliance,short onset of action, reasonably long duration of action, and minimalside effects with few contraindications, as compared to agents nowavailable.

There is also a continuing need for improved pharmacological agents forthe treatment of diabetes and obesity.

It is therefore an object of the present invention to provide bridgedpiperidine derivatives which are melanocortin receptor agonists andthereby useful to treat obesity, diabetes, male sexual dysfunction, andfemale sexual dysfunction.

It is another object of the present invention to provide bridgedpiperidine derivatives which are selective agonists of themelanocortin-4 (MC-4R) receptor.

It is another object of the present invention to provide pharmaceuticalcompositions comprising the melanocortin receptor agonists of thepresent invention with a pharmaceutically acceptable carrier.

It is another object of the present invention to provide methods for thetreatment or prevention of disorders, diseases, or conditions responsiveto the activation of the melanocortin receptor in a subject in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

It is another object of the present invention to provide methods for thetreatment or prevention of obesity, diabetes mellitus, male sexualdysfunction, and female sexual dysfunction by administering thecompounds and pharmaceutical compositions of the present invention to asubject in need thereof.

It is another object of the present invention to provide methods for thetreatment of erectile dysfunction by administering the compounds andpharmaceutical compositions of the present invention to a subject inneed thereof.

These and other objects will become readily apparent from the detaileddescription that follows.

SUMMARY OF THE INVENTION

The present invention relates to novel bridged piperidine derivatives ofstructural formula I:

These bridged piperidine derivatives are effective as melanocortinreceptor agonists and are particularly effective as selectivemelanocortin-4 receptor (MC-4R) agonists. They are therefore useful forthe treatment and/or prevention of disorders responsive to theactivation of MC-4R, such as obesity, diabetes as well as male andfemale sexual dysfunction, in particular, male erectile dysfunction.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment orprevention of disorders, diseases, or conditions responsive to theactivation of the melanocortin receptor in a subject in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention.

The present invention also relates to methods for the treatment orprevention of obesity, diabetes mellitus, male sexual dysfunction, andfemale sexual dysfunction by administering the compounds andpharmaceutical compositions of the present invention.

The present invention also relates to methods for treating erectiledysfunction by administering the compounds and pharmaceuticalcompositions of the present invention.

The present invention also relates to methods for treating erectiledysfunction by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treating or preventingobesity by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

The present invention also relates to methods for treating or preventingdiabetes by administering the compounds of the present invention incombination with a therapeutically effective amount of another agentknown to be useful to treat the condition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to bridged piperidine derivatives usefulas melanocortin receptor agonists. Representative compounds of thepresent invention are described by structural formula I:

or a pharmaceutically acceptable salt thereof;

-   wherein m is 1 or 2;-   each n is independently 0, 1, or 2;-   each p is independently 0, 1 or 2;-   q is 1 or 2;-   R¹ is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CHR⁷)_(n)—C₃₋₆ cycloalkyl,    -   (CHR⁷)_(q)—O(CHR⁷)aryl,    -   (CHR⁷)_(n)-aryl, and    -   (CHR⁷)_(n)-heteroaryl;        wherein aryl and heteroaryl are unsubstituted or substituted        with one to three groups independently selected from R⁶; and        alkyl and cycloalkyl are unsubstituted or substituted with one        to three groups independently selected from R⁶ and oxo;-   R² is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)C₃₋₆ cycloalkyl, and    -   (CH₂)_(n)-aryl;-   R³ and R⁴ are each independently selected from the group consisting    of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)C₃₋₆ cycloalkyl,    -   (CH₂)_(n)-aryl,    -   hydroxy,    -   halogen, and    -   amino;-   R⁵ is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)C₃₋₆ cycloalkyl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl,    -   COC(R⁷)₂NH₂,    -   COR⁷,    -   (CH₂)_(n)OR⁷,    -   (CH₂)_(n)CO₂R⁷,    -   (CH₂)_(n)CONR⁷R⁷,    -   CH₂C≡CH,    -   CO₂R⁷,    -   CH₂CHF₂,    -   CONR⁷R⁷, and    -   SO₂R⁷;        wherein aryl and heteroaryl are unsubstituted or substituted        with one to three groups independently selected from R⁶; and        alkyl, cycloalkyl, and heterocyclyl are unsubstituted or        substituted with one to three groups independently selected from        R⁶ and oxo;-   each R⁶ is independently selected from the group consisting of    -   hydrogen,    -   C₁₋₆ alkyl,    -   (CH₂)_(n)-phenyl,    -   (CH₂)_(n)-naphthyl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl,    -   (CH₂)_(n)C₃₋₇ cycloalkyl,    -   halogen,    -   OR⁷,    -   (CH₂)_(n)N(R⁷)₂,    -   (CH₂)_(n)C≡N,    -   (CH₂)_(n)CO₂R⁷,    -   NO₂,    -   (CH₂)_(n)NR⁷SO₂R⁷,    -   (CH₂)_(n)SO₂N(R⁷)₂,    -   (CH₂)_(n)S(O)_(p)R⁷,    -   (CH₂)_(n)NR⁷C(O)N(R⁷)₂,    -   (CH₂)_(n)C(O)N(R⁷)₂,    -   (CH₂)_(n)NR⁷C(O)R⁷,    -   (CH₂)_(n)NR⁷CO₂R⁷,    -   O(CH₂)_(n)C(O)N(R⁷)₂,    -   CF₃,    -   CH₂CF₃,    -   OCF₃, and    -   OCH₂CF₃;        wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and        heterocyclyl are unsubstituted or substituted with one to three        substituents independently selected from halogen, hydroxy, C₁₋₄        alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any        methylene (CH₂) carbon atom in R⁶ is unsubstituted or        substituted with one to two groups independently selected from        halogen, hydroxy, and C₁₋₄ alkyl; or two substituents when on        the same methylene (CH₂) carbon atom are taken together with the        carbon atom to which they are attached to form a cyclopropyl        group;-   each R⁷ is independently selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)-phenyl,    -   (CH₂)_(n)-naphthyl,    -   (CH₂)_(n)-heteroaryl, and    -   (CH₂)_(n)C₃₋₇ cycloalkyl;        wherein phenyl, naphthyl, and heteroaryl are unsubstituted or        substituted with one to three groups independently selected from        R⁶; alkyl and cycloalkyl are unsubstituted or substituted with        one to three groups independently selected from R⁶ and oxo; and        wherein any methylene (CH₂) carbon atom in R⁷ is unsubstituted        or substituted with one to two groups independently selected        from halogen, hydroxy, and C₁₋₄ alkyl; or two R⁷ groups together        with the atom to which they are attached form a 5- to 8-membered        mono- or bicyclic ring system optionally containing an        additional heteroatom selected from O, S, and NC₁₋₄ alkyl;-   each R⁸ is independently selected from the group consisting of    -   hydrogen,    -   (CH₂)_(n)C₁₋₇ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl, and    -   (CH₂)_(n)C₃₋₇ cycloalkyl;        wherein aryl and heteroaryl are unsubstituted or substituted        with one to three groups independently selected from R⁶; and        alkyl, cycloalkyl, heterocyclyl, and (CH₂)_(n) are unsubstituted        or substituted with one to three groups independently selected        from R⁶ and oxo; or two substituents when on the same methylene        (CH₂) carbon atom are taken together with the carbon atom to        which they are attached to form a cyclopropyl group;-   or two R⁸ groups together with the atoms to which they are attached    form a 5- to 8-membered mono- or bi-cyclic ring system optionally    containing an additional heteroatom selected from O, S, NR⁷, NBoc,    and NCbz;-   X is selected from the group consisting of    -   C₁₋₁₈ alkyl,    -   (CH₂)_(n)C₃₋₈ cycloalkyl,    -   (CH₂)_(n)-phenyl,    -   (CH₂)_(n)-naphthyl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)heterocyclyl,    -   (CH₂)_(n)C≡N,    -   (CH₂)_(n)CON(R⁸R⁸),    -   (CH₂)_(n)CO₂R⁸,    -   (CH₂)_(n)COR⁸,    -   (CH₂)_(n)NR⁸C(O)R⁸,    -   (CH₂)_(n)NR⁸CO₂R⁸,    -   (CH₂)_(n)NR⁸C(O)N(R⁸)₂,    -   (CH₂)_(n)NR⁸SO₂R⁸,    -   (CH₂)_(n)S(O)_(p)R⁸,    -   (CH₂)_(n)SO₂N(R⁸)(R⁸),    -   (CH₂)_(n)OR⁸,    -   (CH₂)_(n)OC(O)R⁸,    -   (CH₂)_(n)OC(O)OR⁸,    -   (CH₂)_(n)OC(O)N(R⁸)₂,    -   (CH₂)_(n)N(R⁸)(R⁸), and    -   (CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸);-   wherein phenyl, naphthyl, and heteroaryl are unsubstituted or    substituted with one to three groups independently selected from R⁶;    alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted    with one to three groups independently selected from R⁶ and oxo; and    wherein any methylene (CH₂) carbon atom in X is unsubstituted or    substituted with one to two groups independently selected from    halogen, hydroxy, and C₁₋₄ alkyl; and-   Y is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   C₂₋₆ alkenyl,    -   (CH₂)_(n)C₃₋₈ cycloalkyl,    -   (CH₂)_(n)-phenyl,    -   (CH₂)_(n)-naphthyl,    -   (CH₂)_(n)-heteroaryl, and    -   (CH₂)_(n)-heterocyclyl;        wherein phenyl, naphthyl, and heteroaryl are unsubstituted or        substituted with one to three groups independently selected from        R⁶; alkyl, cycloalkyl, and heterocyclyl are optionally        substituted with one to three groups independently selected from        R⁶ and oxo; and wherein any methylene (CH₂) carbon atom in Y is        unsubstituted or substituted with one to two groups        independently selected from halogen, hydroxy, and C₁₋₄ alkyl.

In one embodiment of the compounds of formula I, R¹ is CHR⁷-aryl,CHR⁷OCHR⁷-aryl, or CHR⁷-heteroaryl wherein aryl and heteroaryl areunsubstituted or substituted with one to two groups independentlyselected from R⁶. In a class of this embodiment, R¹ is benzyl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, CF₃, and OCF₃. In a subclass of this class,R¹ is 4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl;3,5-difluorobenzyl; 2-cyano-4-fluorobenzyl; or 4-methoxybenzyl.

In a second embodiment of compounds of formula I, R² is hydrogen or CH₃.

In a third embodiment of compounds of formula I, R⁵ is selected from thegroup consisting of

-   -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl,    -   (CH₂)_(n)C₃₋₆ cycloalkyl,    -   (CH₂)_(n)CO₂R⁷,    -   (CH₂)_(n)CONR⁷R⁷,    -   (CH₂)_(n)OR⁷,    -   COC(R⁷)NH₂,    -   CH₂C≡CH, and    -   CH₂CHF₂;        wherein aryl and heteroaryl are unsubstituted or substituted        with one to three groups independently selected from R⁶; and        alkyl, cycloalkyl, and heterocyclyl are unsubstituted or        substituted with one to three groups independently selected from        R⁶ and oxo.

In a fourth embodiment of compounds of formula I, X is C₁₋₆ alkyl,(CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl,(CH₂)_(n)C(O)N(R⁸)(R⁸), (CH₂)_(n)CO₂R⁸, (CH₂)_(n)OR⁸,(CH₂)_(n)S(O)₀₋₂R⁸, (CH₂)_(n)NHC(O)R⁸, (CH₂)_(n)OC(O)NR⁸R⁸, or(CH₂)_(n)NR⁸SO₂R⁸; wherein aryl and heteroaryl are optionallysubstituted with one to three groups independently selected from R⁶;heterocyclyl is optionally substituted with one to three groupsindependently selected from R⁶ and oxo; the (CH₂)_(n) group isoptionally substituted with one to three groups independently selectedfrom R⁷, halogen, S(O)₀₋₂R⁷, N(R⁷)₂, and OR⁷; and each R⁸ isindependently selected from H, C₁₋₈ alkyl, and C₃₋₆ cycloalkyl, whereinalkyl and cycloalkyl are optionally substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono- orbi-cyclic ring system optionally containing an additional heteroatomselected from O, S, NR⁷, NBoc, and NCbz.

In a class of this fourth embodiment, X is C₁₋₆ alkyl,(CH₂)₀₋₁-heteroaryl, CH₂-heterocyclyl, CO₂R⁸, CH₂OR⁸, CH₂S(O)₀₋₂R⁸,NHC(O)R⁸, CH₂NR⁸SO₂R⁸, CH₂OC(O)NR⁸R⁸, CH₂NR⁸SO₂R⁸, or C(O)N(R⁸)(R⁸);wherein heteroaryl is optionally substituted with one to three groupsindependently selected from R⁶; heterocyclyl is optionally substitutedwith one to three groups independently selected from R⁶ and oxo; andeach R⁸ is independently selected from H, C₁₋₈ alkyl, and C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted withone to three groups independently selected from R⁶ and oxo; or two R⁸groups together with the atoms to which they are attached form a 5- to8-membered mono- or bi-cyclic ring system optionally containing anadditional heteroatom selected from O, S, NR⁷, NBoc, and NCbz.

In a fifth embodiment of compounds of formula I, Y is C₁₋₈ alkyl,(CH₂)_(n)C₃₋₇ cycloalkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heterocyclyl, or(CH₂)_(n)-heteroaryl; wherein aryl and heteroaryl are optionallysubstituted with one to three groups independently selected from R⁶; and(CH₂)_(n), alkyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one to three groups independently selected from R⁶ andoxo. In a class of this embodiment, Y is cyclohexyl, cycloheptyl,cyclopentyl, or C₁₋₆ alkyl, wherein alkyl and cycloalkyl areunsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo. In a subclass of this class, Y is cyclohexylor C₁₋₆ alkyl, wherein the cyclohexyl and alkyl groups are unsubstitutedor substituted with one to three groups independently selected from R⁶and oxo.

In yet a further embodiment of the present invention, there are providedcompounds of structural formula II:

-   wherein m is 1 or 2;-   each n is independently 0, 1, or 2;-   R² is hydrogen or methyl;-   R³ is hydrogen, fluoro, or hydroxy;-   each R⁶ is independently selected from the group consisting of    -   hydrogen,    -   halogen,    -   cyano,    -   C₁₋₄ alkyl,    -   C₁₋₄ alkoxy,    -   trifluoromethyl, and    -   trifluoromethoxy;-   R⁵ is selected from the group consisting of    -   hydrogen,    -   C₁₋₈ alkyl,    -   (CH₂)_(n)-aryl,    -   (CH₂)_(n)-heteroaryl,    -   (CH₂)_(n)-heterocyclyl,    -   (CH₂)_(n)C₃₋₆ cycloalkyl,    -   (CH₂)_(n)CO₂R⁷,    -   (CH₂)_(n)CONR⁷R⁷,    -   (CH₂)_(n)OR⁷,    -   COC(R⁷)NH₂,    -   CH₂C≡CH, and    -   CH₂CHF₂;        wherein aryl and heteroaryl are unsubstituted or substituted        with one to three groups independently selected from R⁶; and        alkyl, cycloalkyl, and heterocyclyl are unsubstituted or        substituted with one to three groups independently selected from        R⁶ and oxo;-   Y is selected from the group consisting of    -   C₅₋₇ cycloalkyl and    -   C₁₋₆ alkyl;        wherein alkyl and cycloalkyl are unsubstituted or substituted        with one to three groups independently selected from R⁶ and oxo;        and-   X is selected from the group consisting of

-   —NHC(O)tBu; —C(O)NHCH(Et)₂; —C(O)NHCH₂tBu;

-    —CH₂SCH(CH₃)₂; —CH₂S(O)CH(CH₃)₂; —CH₂S(O)₂CH(CH₃)₂;    —C(O)NHCH₂CH₂N(CH₃)₂; C(O)CH(CH₃)₂; —CH₂NHCOtBu; —CH₂OC(O)NMe₂;    —CH₂C(O)NEt₂; —CH₂OC(Me)₂CO₂H; —C(O)NHC(Me)₂CO₂Me;    —C(O)NHC(Me)₂CO₂H; —CH₂N(CH₃)COtBu; —CH₂N(iPr)COMe; —CH₂N(iPr)SO₂Me;    C(O)NHC(Me)₂CH₂OMe; C(O)NHC(Me)₂CH₂OH; —CH₂CH₂C(Me)₂OH;

In a class of this embodiment of compounds of formula II, the carbonatom marked with * has the R configuration.

Representative compounds of the present invention of structural formulaI having the indicated R stereochemistry at the stereogenic centermarked with an * and the indicated anti stereochemistry at thestereogenic center marked with an ** relative to the [2.2.1]-bicyclering nitrogen are as follows:

Diastereomer with X R⁶ anti-stereochem at** R⁵

Cl d₁ H

Cl d₂ H

F d₁ + d₂ H

F d₁ + d₂ iPr

F d₁ H

F d₂ H

F d₁ iPr

F d₂ iPr

Further illustrative of compounds of the present invention of structuralformula I having the indicated R stereochemistry at the stereogeniccenter marked with an * and the indicated anti stereochemistry at thestereogenic center marked with an ** relative to the [2.2.2]-bicyclering nitrogen are as follows:

Diastereomer with anti-stereo- X R⁶ chem at ** R⁵

F d₁ + d₂ H

F d₂ Me

F d₁ + d₂ iPr

F d₁ + d₂ cyclobutyl

F d₁ + d₂

F d₁ —CH₂CO₂H

F d₁ —CH₂CONH₂

F d₁

F d₁

F d₁ —COCH₂NH₂

F d₁ + d₂ H

Cl d₁ + d₂ Me

Cl d₁ + d₂ iPr

F d₁ + d₂ cyclobutyl

F d₁ 2,2-difluoroethyl

F d₁

Cl d₁ + d₂ H

Cl d₁ + d₂ H

F d₁ + d₂ H

Cl d₁ + d₂ H

F d₁ + d₂ iPr

F d₁ + d₂ H

F d₁ Me

F d₁ + d₂ H

F d₁ + d₂ cyclobutyl

F d₁ + d₂ Me

F d₁ + d₂ Me

Yet further illustrative are the compounds selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.

The compounds of structural formula I are effective as melanocortinreceptor agonists and are particularly effective as selective agonistsof MC-4R. They are therefore useful for the treatment and/or preventionof disorders responsive to the activation of MC-4R, such as obesity,diabetes as well as male and/or female sexual dysfunction, inparticular, erectile dysfunction, and further in particular, maleerectile dysfunction.

Another aspect of the present invention provides a method for thetreatment or prevention of obesity or diabetes in a subject in needthereof which comprises administering to said subject a therapeuticallyor prophylactically effective amount of a compound of structural formulaI.

Another aspect of the present invention provides a method for thetreatment or prevention of male or female sexual dysfunction includingerectile dysfunction which comprises administering to a subject in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a compound of structural formula I.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of structural formula I and apharmaceutically acceptable carrier.

Yet another aspect of the present invention provides a method for thetreatment or prevention of male or female sexual dysfunction includingerectile dysfunction which comprises administering to a subject in needof such treatment or prevention a therapeutically or prophylacticallyeffective amount of a compound of structural formula I in combinationwith a therapeutically effective amount of another agent known to beuseful for the treatment of these conditions.

Yet another aspect of the present invention provides a method for thetreatment or prevention of obesity which comprises administering to asubject in need of such treatment or prevention a therapeutically orprophylactically effective amount of a compound of structural formula Iin combination with a therapeutically effective amount of another agentknown to be useful for the treatment of this condition.

Throughout the instant application, the following terms have theindicated meanings:

The alkyl groups specified above are intended to include those alkylgroups of the designated length in either a straight or branchedconfiguration. Exemplary of such alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl,isohexyl, and the like.

The term “halogen” is intended to include the halogen atoms fluorine,chlorine, bromine and iodine.

The term “C₁₋₄ alkyliminoyl” means C13C(═NH)—.

The term “aryl” includes phenyl and naphthyl.

The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. “5- or 6-Membered heteroaryl” represents a monocyclicheteroaromatic ring; examples thereof include thiazole, oxazole,thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole,thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine,pyrazine, and the like. Bicyclic heteroaromatic rings include, but arenot limited to, benzothiadiazole, indole, benzothiophene, benzofuran,benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole,benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.

The term “5- or 6-membered carbocyclyl” is intended to includenon-aromatic rings containing only carbon atoms such as cyclopentyl andcyclohexyl.

The term “5 and 6-membered heterocyclyl” is intended to includenon-aromatic heterocycles containing one to four heteroatoms selectedfrom nitrogen, oxygen and sulfur. Examples of a 5 or 6-memberedheterocyclyl include piperidine, morpholine, thiamorpholine,pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example, NR⁷R⁷ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

“Erectile dysfunction” is a disorder involving the failure of a malemammal to achieve erection, ejaculation, or both. Symptoms of erectiledysfunction include an inability to achieve or maintain an erection,ejaculatory failure, premature ejaculation, or inability to achieve anorgasm. An increase in erectile dysfunction is often associated with ageand is generally caused by a physical disease or as a side-effect ofdrug treatment.

By a melanocortin receptor “agonist” is meant an endogenous or drugsubstance or compound that can interact with a melanocortin receptor andinitiate a pharmacological response characteristic of the melanocortinreceptor. By a melanocortin receptor “antagonist” is meant a drug or acompound that opposes the melanocortin receptor-associated responsesnormally induced by another bioactive agent. The “agonistic” propertiesof the compounds of the present invention were measured in thefunctional assay described below. The functional assay discriminates amelanocortin receptor agonist from a melanocortin receptor antagonist.

By “binding affinity” is meant the ability of a compound/drug to bind toits biological target, in the the present instance, the ability of acompound of structural formula I to bind to a melanocortin receptor.Binding affinities for the compounds of the present invention weremeasured in the binding assay described below and are expressed asIC₅₀'s.

“Efficacy” describes the relative intensity with which agonists vary inthe response they produce even when they occupy the same number ofreceptors and with the same affinity. Efficacy is the property thatenables drugs to produce responses. Properties of compounds/drugs can becategorized into two groups, those which cause them to associate withthe receptors (binding affinity) and those that produce a stimulus(efficacy). The term “efficacy” is used to characterize the level ofmaximal responses induced by agonists. Not all agonists of a receptorare capable of inducing identical levels of maximal responses. Maximalresponse depends on the efficiency of receptor coupling, that is, fromthe cascade of events, which, from the binding of the drug to thereceptor, leads to the desired biological effect.

The functional activities expressed as EC₅₀'s and the “agonist efficacy”for the compounds of the present invention at a particular concentrationwere measured in the functional assay described below.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of structural formula I contain one or more asymmetric centersand can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of structural formula I. Thus, the present invention is meantto encompass the stereoisomers depicted in the following structuralformulae:

wherein the stereochemistry at the stereogenic center marked with an *can be either R or S.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers such asketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed within the compounds of structural formula I.

Compounds of structural formula I may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general formula Iand II may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known absolute configuration.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Utility

Compounds of formula I are melanocortin receptor agonists and as suchare useful in the treatment, control or prevention of diseases,disorders or conditions responsive to the activation of one or more ofthe melanocortin receptors including, but are not limited to, MC-1,MC-2, MC-3, MC-4, or MC-5. Such diseases, disorders or conditionsinclude, but are not limited to, obesity (by reducing appetite,increasing metabolic rate, reducing fat intake or reducing carbohydratecraving), diabetes mellitus (by enhancing glucose tolerance, decreasinginsulin resistance), hypertension, hyperlipidemia, osteoarthritis,cancer, gall bladder disease, sleep apnea, depression, anxiety,compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain,male and female sexual dysfunction (including impotence, loss of libidoand erectile dysfunction), fever, inflammation, immunemodulation,rheumatoid arthritis, skin tanning, acne and other skin disorders,neuroprotective and cognitive and memory enhancement including thetreatment of Alzheimer's disease. Some compounds encompassed by formulaI show highly selective affinity for the melanocortin-4 receptorrelative to MC-1R, MC-2R, MC-3R, and MC-5R, which makes them especiallyuseful in the prevention and treatment of obesity, as well as maleand/or female sexual dysfunction, including erectile dysfunction.

“Male sexual dysfunction” includes impotence, loss of libido, anderectile dysfunction.

“Erectile dysfunction” is a disorder involving the failure of a malemammal to achieve erection, ejaculation; or both. Symptoms of erectiledysfunction include an inability to achieve or maintain an erection,ejaculatory failure, premature ejaculation, or inability to achieve anorgasm. An increase in erectile dysfunction and sexual dysfunction canhave numerous underlying causes, including but not limited to (1) aging,(b) an underlying physical dysfunction, such as trauma, surgery, andperipheral vascular disease, and (3) side-effects resulting from drugtreatment, depression, and other CNS disorders.

“Female sexual dysfunction” can be seen as resulting from multiplecomponents including dysfunction in desire, sexual arousal, sexualreceptivity, and orgasm related to disturbances in the clitoris, vagina,periurethral glans, and other trigger points of sexual function. Inparticular, anatomic and functional modification of such trigger pointsmay diminish the orgasmic potential in breast cancer and gynecologiccancer patients. Treatment of female sexual dysfunction with an MC-4receptor agonist can result in improved blood flow, improvedlubrication, improved sensation, facilitation of reaching orgasm,reduction in the refractory period between orgasms, and improvements inarousal and desire. In a broader sense, “female sexual dysfunction” alsoincorporates sexual pain, premature labor, and dysmenorrhea.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally or topically.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating obesity, in conjunction with diabetes and/orhyperglycemia, or alone, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from about 0.001 milligram to about 100 milligrams perkilogram of animal body weight, preferably given in a single dose or individed doses two to six times a day, or in sustained release form. Inthe case of a 70 kg adult human, the total daily dose will generally befrom about 0.07 milligrams to about 3500 milligrams. This dosage regimenmay be adjusted to provide the optimal therapeutic response:

When treating diabetes mellitus and/or hyperglycemia, as well as otherdiseases or disorders for which compounds of formula I are useful,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.001milligram to about 100 milligram per kilogram of animal body weight,preferably given in a single dose or in divided doses two to six times aday, or in sustained release form. In the case of a 70 kg adult human,the total daily dose will generally be from about 0.07 milligrams toabout 350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

For the treatment of sexual dysfunction compounds of the presentinvention are given in a dose range of 0.001 milligram to about 100milligram per kilogram of body weight, preferably as a single doseorally or as a nasal spray.

Combination Therapy

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases or conditions for which compounds of Formula I are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of Formula I is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of Formula I.

Examples of other active ingredients that may be combined with acompound of Formula I for the treatment or prevention of obesity and/ordiabetes, either administered separately or in the same pharmaceuticalcompositions, include, but are not limited to:

(a) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115,97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;

(b) insulin or insulin mimetics;

(c) sulfonylureas, such as tolbutamide and glipizide;

(d) α-glucosidase inhibitors (such as acarbose),

(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, andother statins), (ii) sequestrants (cholestyramine, colestipol and adialkylaminoalkyl derivatives of a cross-linked dextran), (ii) nicotinylalcohol nicotinic acid or a salt thereof, (iii) proliferator-activaterreceptor α agonists such as fenofibric acid derivatives (gemfibrozil,clofibrate, fenofibrate and benzafibrate), (iv) inhibitors ofcholesterol absorption for example beta-sitosterol and (acylCoA:cholesterol acyltransferase) inhibitors for example melinamide, (v)probucol, (vi) vitamin E, and (vii) thyromimetics;

(f) PPARδ agonists, such as those disclosed in WO97/28149;

(g) anti-obesity serotonergic agents, such as fenfluramine,dexfenfluramine, phentermine, and sibutramine;

(h) β3-adrenoreceptor agonists;

(i) pancreatic lipase inhibitors, such as orlistat;

(j) feeding behavior modifying agents, such as neuropeptideY Y1 and Y5antagonists, such as those disclosed in WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 01/14376, and U.S. Pat. No.6,191,160;

(k) orexin-1 receptor antagonists;

(l) PPARα agonists such as described in WO 97/36579 by Glaxo;

(m) PPARγ antagonists as described in WO97/10813;

(n) serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline;

(o) growth hormone secretagogues, such as MK-0677;

(p) cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, and

(q) protein tyrosine phosphatase-1B (PTP-1B) inhibitors.

Examples of anti-obesity agents that can be employed in combination witha compound of Formula I are disclosed in “Patent focus on newanti-obesity agents,” Exp. Opin. Ther. Patents, 10: 819–831 (2000) andin “Novel anti-obesity drugs,” Exp. Opin. Invest. Drugs, 9: 1317–1326(2000). The role of neuropeptide Y in obesity is discussed in Exp. Opin.Invest. Drugs, 9: 1327–1346 (2000). Cannabinoid receptor ligands arediscussed in Exp. Opin. Invest. Drugs, 9: 1553–1571 (2000).

Examples of other active ingredients that may be combined with acompound of Formula I for the treatment or prevention of male or femalesexual dysfunction, in particular, male erectile dysfunction, eitheradministered separately or in the same pharmaceutical compositions,include, but are not limited to (a) type V cyclic-GMP-specificphosphodiesterase (PDE-V) inhibitors, including sildenafil and(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(IC-351); (b) alpha-adrenergic receptor antagonists, includingphentolamine and yohimbine or pharmaceutically acceptable salts thereof;(c) dopamine receptor agonists, such as apomorphine or pharmaceuticallyacceptable salts thereof; and (d) nitric oxide (NO) donors.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I as an activeingredient or a pharmaceutically acceptable salt thereof, and may alsocontain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases or acids including inorganic bases or acids and organic bases oracids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Preparation of Compounds of the Invention

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified by thefollowing specific examples. Moreover, by utilizing the proceduresdescribed in detail in PCT International Application Publications WO99/64002 (16 Dec. 1999) and WO 00/74679 (14 Dec. 2000), which areincorporated by reference herein in their entirety, in conjunction withthe disclosure contained herein, one of ordinary skill in the art canreadily prepare additional compounds of the present invention claimedherein. The compounds illustrated in the examples are not, however, tobe construed as forming the only genus that is considered as theinvention. The Examples further illustrate details for the preparationof the compounds of the present invention. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds. The instant compounds are generally isolated in the form oftheir pharmaceutically acceptable salts, such as those describedpreviously hereinabove. The free amine bases corresponding to theisolated salts can be generated by neutralization with a suitable base,such as aqueous sodium hydrogencarbonate, sodium carbonate, sodiumhydroxide, and potassium hydroxide, and extraction of the liberatedamine free base into an organic solvent followed by evaporation. Theamine free base isolated in this manner can be further converted intoanother pharmaceutically acceptable salt by dissolution in an organicsolvent followed by addition of the appropriate acid and subsequentevaporation, precipitation, or crystallization. All temperatures aredegrees Celsius unless otherwise noted. Mass spectra (MS) were measuredby electron-spray ion-mass spectroscopy.

The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using an acid activating agentsuch as EDC, DCC, and BOP in an inert solvent such as dichloromethane inthe presence of a catalyst such as HOBT. The use of protecting groupsfor the amine and carboxylic acid functionalities to facilitate thedesired reaction and minimize undesired reactions is well documented.Conditions required to remove protecting groups are found in standardtextbooks such as Greene, T, and Wuts, P. G. M., Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZand BOC are commonly used protecting groups in organic synthesis, andtheir removal conditions are known to those skilled in the art. Forexample, CBZ may be removed by catalytic hydrogenation in the presenceof a noble metal or its oxide such as palladium on activated carbon in aprotic solvent such as methanol or ethanol. In cases where catalytichydrogenation is contraindicated due to the presence of otherpotentially reactive functionalities, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in acetic acidor by treatment with a mixture of TFA and dimethylsulfide. Removal ofBOC protecting groups is carried out with a strong acid, such astrifluoroacetic acid, hydrochloric acid, or hydrogen chloride gas, in asolvent such as methylene chloride, methanol, or ethyl acetate.

Abbreviations used in the Description of the Preparation of theCompounds of the Present Invention:

BOC (boc) t-butyloxycarbonyl BOPbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphateBu butyl calc. calculated CBZ (Cbz) benzyloxycarbonyl c-hex cyclohexylc-pen cyclopentyl c-pro cyclopropyl DEAD diethyl azodicarboxylate DIEAdiisopropylethylamine DMAP 4-dimethylaminopyridine DMFN,N-dimethylformamide EDC 1-(3-dimethylaminopropyl)3-ethylcarbodiimideHCl eq. equivalent(s) ES-MS electron spray ion-mass spectroscopy Etethyl EtOAc ethyl acetate HATUO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HOAt 1-hydroxy-7-azabenzotriazole HOBt1-hydroxybenzotriazole hydrate HPLC high performance liquidchromatography LDA lithium diisopropylamide MC-xR melanocortin receptor(x being a number) Me methyl MF molecular formula MS mass spectrum Msmethanesulfonyl OTf trifluoromethanesulfonyl Ph phenyl Phe phenylalaninePr propyl prep. prepared PyBrop bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate r.t. room temperature TFA trifluoroacetic acid THFtetrahydrofuran TLC thin-layer chromatography.

Reaction Schemes A and B illustrate the methods employed in thesynthesis of the compounds of the present invention of structuralformula I. All substituents are as defined above unless indicatedotherwise.

Reaction Scheme A illustrates a key step in the synthesis of the novelcompounds of structural formula I of the present invention. As shown inreaction Scheme A, the reaction of a 4-substituted piperidine of generalformula 1 with an amino acid derivative of general formula 2 followed byremoval of the amine protecting group Q affords an intermediate amine ofgeneral formula 3. The amine of formula 3 is then coupled with anN-protected bridged piperidine carboxylic acid of general formula 4 toafford a protected dipeptide of general formula 5. The two amide bondcoupling reactions illustrated in reaction Scheme A are conducted in anappropriate inert solvent such as dimethylformamide (DMF), methylenechloride or the like and may be performed with a variety of reagentssuitable for amide coupling reactions such asO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophospbate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) orbenzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate(PyBOP). Preferred conditions for the amide bond coupling reactionsshown in reaction Scheme A are known to those skilled in organicsynthesis. Such modifications may include, but are not limited to, theuse of basic reagents such as triethylamine (TEA) or N-methylmorpholine(NMM), or the addition of an additive such as1-hydroxy-7-azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt).Alternatively, 4-substituted piperidines of formula 1 may be treatedwith an active ester or acid chloride derived from carboxylic acid 2 or4 which also affords compounds of structural formula I. The amide bondcouplings shown in reaction Scheme A are usually conducted attemperatures between 0° C. and room temperature, occasionally atelevated temperatures, and the coupling reactions are typicallyconducted for periods of 1 to 24 hours.

If it is desired to produce a compound of structural formula I whereinR⁵ is a hydrogen, the N-BOC or N-Cbz protected, analogs of structuralformula I may be used in the synthesis and either Boc-deprotected underacidic conditions, for instance using trifluoroacetic acid in a solventlike methylene chloride or hydrogen chloride in a solvent such as ethylacetate at room temperature, or Cbz-deprotected by catalytichydrogenation.

When it is desired to prepare compounds of structural formula I whereinR⁵ is not a hydrogen, the compounds of general formula I (R⁵=H) may befurther modified using the methodology described below in reactionScheme B.

Reaction Scheme B illustrates general methods for the elaboration of anR⁵ substituent following assembly of a compound of structural formula I(wherein R⁵=BOC or Cbz) as described in reaction Scheme A. Either theN-BOC protected compound of structural formula I is first deprotectedunder acidic conditions for instance by treatment with hydrogen chloridein ethyl acetate or using trifluoroacetic acid in dichloromethane, orthe N-Cbz protected compound is deprotected by catalytic hydrogenation.The resulting heterocyclic compound of structural formula I (R⁵=H) maythen be subjected to one of several alkylation strategies known inorganic chemistry. For instance, compounds ([) (R⁵=H) may be utilized ina reductive amination reaction with a suitable carbonyl containingpartner (6). The reductive amination is achieved by initial formation ofan imine between the amine of formula I (R⁵=H) and either an aldehyde orketone of formula 6. The intermediate imine is then treated with areducing agent capable of reducing carbon-nitrogen double bonds such assodium cyanoborohydride or sodium triacetoxyborohydride and an alkylatedproduct of structural formula I is produced. Alternatively, aheterocyclic compound of structural formula (I) (R⁵=H) may be directlyalkylated using an alkylating agent such as 7 in a polar aprotic solventsuch as DMF. In this reaction, the substituent Z of compound 7 is a goodleaving group such as a halide, mesylate or triflate and the product isthe compound of structural formula I bearing the R⁵ substituent.

Preparation of N-Protected Bridged Piperidines of General Formula 4:

The N-protected bridged piperidine intermediates of general formula 4for coupling with a peptide of general formula 3 as in Scheme A can beobtained from commercial sources or can be prepared following proceduresdescribed in the published chemical literature or modifications thereofthat are in the purview of one of ordinary skill in the art of syntheticorganic chemistry.

Preparation of 4-Substituted Piperidine Intermediates General Formula 1:

The preparation of 4-substituted piperidine intermediates of generalstructure 1 in Scheme A for coupling with the appropriate carboxylicacid intermediates of general structure 2 in Scheme A is disclosed inPCT International Application WO 00/74679 (14 Dec. 2000), which isincorporated by reference herein in its entirety. The synthesis ofadditional 4-substituted piperidine intermediates needed to prepare thecompounds of the present invention is provided below.

Piperidine Intermediate 1:

To a solution of 4-cyclohexyl4-formyl-N-(tertbutyloxycarbonyl)piperidine (2.56 g, 8.68 mmol) intoluene (100 ml) was added acetic acid (2 ml) and1-amino-1-cyclopentanemethanol (1.0 g, 8.68 mmol). After refluxing byusing a Dean-Stark apparatus for 11 hours, the reaction mixture wasconcentrated. The residue was dissolved in acetic acid (70 ml) andhydrogenated overnight in the presence of platinum oxide (500 mg) undera balloon atmosphere of hydrogen gas. The catalyst was filtered off andsolvent was removed to give a colorless oil, which was dissolved inmethanol and made basic by addition of NaOH(5N, 4 ml) and concentrated.The residue was partitioned between water and CH₂Cl₂, the two layersseparated, and the aqueous layer extracted with CH₂Cl₂. The combinedorganic extracts were washed with brine, dried over MgSO₄ andconcentrated to give the title compound as a colorless oil (2.1 g).

MS: calc.for C₂₃H₄₂N₂O₃: 394.3; Found: 395 (M+1), 417 (M+Na).

Piperidine Intermediate 2:

To a solution of Intermediate 1 (2.1 g, 5.33 mmol) in CH₂Cl₂ (70 ml) at0° was added DMAP (0.65 g, 5.33 mmol), DIEA (3.76 ml, 21.3 mmol)followed by slow addition of phosgene (4.1 ml, 8.0 mmol). After stirringthe reaction mixture for one hour at 0° C., the ice-water bath wasremoved and the reaction mixture was continued to stir at roomtemperature overnight. The mixture was diluted with CH₂Cl₂, washed withwater and brine, dried over MgSO₄ and concentrated to give crudeproduct, which was purified by column chromatography on silica gel (2%EtOAc/CH₂Cl₂ to 5% EtOAc/CH₂Cl₂) to give the title compound as a whitesolid (1.2 g).

MS: calc.for C₂₄H₄₀N₂O₄: 420.3; Found: (M+1), (M+Na).

Piperidine Intermediate 3:

To the Intermediate 2 (1.2 g) was added hydrogen chloride (4.0 M indioxane). The reaction mixture was stirred at room temperature for 30minutes and the solvent was removed in vacuo to afford the titlecompound (1.2 g).

MS: calc.for C₁₉H₃₂N₂O₂: 320.3; Found: 321.1 (M+H).

Piperidine Intermediate 4:

Intermediate 4 was prepared from (S)-(+)-2-amino-1-propanol in ananalogous manner to the one described for the preparation ofIntermediate 1.

MS: calc.for C₂₀H₃₈N₂O₃: 354; Found: 355 (M+H).

Piperidine Intermediate 5:

Intermediate 5 was prepared from Intermediate 4 in an analogous mannerto the one described for the preparation of Intermediate 2.

MS: calc. for C₂₁H₃₆N₂₀₄: 380.3; Found: 381 (M+H).

Piperidine Intermediate 6:

Intermediate 6 was prepared from Intermediate 5 in an analogous mannerto the one described for the preparation of Intermediate 3.

MS: calc. for C₁₆H₂₈N₂O₂: 280.3; Found: 281 (M+).

Piperidine Intermediate 7:

To a suspension of 1-aminocyclopropane-1-carboxylic acid (2.8 g, 27.7mmol) in THF (20 ml) was added borane-tetrahydrofuran complex (100 ml,100 mmol) slowly under nitrogen at room temperature. The reactionmixture was stirred at 70° C. overnight, then cooled to 0° C. Afteraddition of methanol (12.2 ml, 300 mmol), the mixture was allowed tostir for 30 minutes. Then acetic acid (1.6 ml, 27.7 mmol) was added. Thereaction mixture was concentrated to provide the title compound as acolorless oil (3.0 g).

Piperidine Intermediate 8:

Intermediate 8 was prepared from Intermediate 7 in an analogous mannerto the one described for the preparation of Intermediate 1.

MS: calc. for C₂₁H₃₈N₂O₃: 366.3; Found: 367 (M+H).

Piperidine Intermediate 9:

To a solution of Intermediate 8 (0.8 g, 2.18 mmol) in CH₂Cl₂ (40 ml) at0° was added DMAP (0.266 g, 2.18 mmol), DIEA (1.52 ml, 8.74 mmol) andtriphosgene (0.648 g, 2.18 mmol). After stirring the reaction mixturefor one hour at 0° C., the ice-water bath was removed and the reactionmixture was allowed to stir at r.t. overnight. The mixture was dilutedwith CH₂Cl₂, washed with water and brine, dried over MgSO₄ andconcentrated to give crude product, which was purified by columnchromatography on silica gel (10% CH₂Cl₂/EtOAc) to give the titlecompound as a colorless oil (0.13 g).

ESI-MS: calc. for C₂₂H₃₆N₂O₄: 392; Found: 393 (M+1).

Piperidine Intermediate 10:

Intermediate 10 was prepared from Intermediate 9 in an analogous mannerto the one described for the preparation of Intermediate 3.

MS: calc. for C₁₇H₂₈N₂O₂: 292.2; Found: 293 (M+H).

Piperidine Intermediate 11:

To a solution of the alcohol (9.41 g, 31.6 mmol) in CH₂Cl₂ (100 ml) at0° C. containing molecular sieves (2 g) and 4-methylmorpholine N-oxideAMMO) (4.449 g, 37.98 mmol) was added TPAP (1.12 g, 3.16 mmol). Afterstirring the reaction mixture at 0° C. for 0.5 h, the reaction mixturewas warmed to room temperature and stirred further for 5 hrs. Thereaction mixture was concentrated to half the volume, diluted withhexane (250 ml), filtered through a silica gel pad and concentrated togive pure title compound (9.4 g).

Piperidine Intermediate 12:

To a solution of the aldehyde (2 g, 6.7 mmol) in toluene (50 ml) wasadded acetic acid (500 μl). After stirring the reaction mixture atreflux temperature using Dean Stark apparatus for 8 hrs, the mixture wasconcentrated and dissolved in acetic acid (30 ml). To the mixture wasadded PtO₂ (500 mg) which was stirred under an atmosphere of H₂overnight. The rection mixture was flushed with nitrogen, filtered andconcentrated to give the title compound (2 g).

Piperidine Intermediate 13:

To a solution of the amino alcohol (4.96 g, 13.47 mmol) in CH₂Cl₂ at 0°C. containing DIEA (6.98 g, 53.9 mmol), DMAP (1.64 g, 13.47 mmol) wasadded slowly a toluene solution of phosgene (1.93M, 10.47 ml, 20.21mmol). After stirring the reaction mixture for 1 hr at 0° C., thetemperature was raised to room temperarure and stirred further for 2hrs. The reaction mixture was diluted with CH₂Cl₂, washed with water,brine, dried and concentrated. The residue was purified by columnchromatography over silica gel (5% EtOAc/CH₂Cl₂) to give pure product(3.95 g).

Piperidine Intermediate 14:

To a solution of Intermediate 13 (3.95 g) in CH₂Cl₂ was added 5 ml of asaturated HCl solution of EtOAc. After stirring the reaction mixture for30 minutes at room temperature, the solvent was removed and the residuelyophilized from a benzene/methanol solution to afford the titlecompound (3.85 g).

Piperidine Intermediate 15:

To a suspension of the alcohol (29 g, 97.5 mmol),4-methylmorpholine-N-oxide (15.8 g, 134.6 mmol), and molecular sieves(15.0 gm) in DCM (500 mL) was added tetrapropylammonium perruthenate(TPAP, 1.03 g, 2.92 mmol) portionwise at room temperature. The mixturewas stirred at room temperature for 30 min and TLC showed the reactionwas completed. The mixture was filtered through a pad of silica gel,washed with DCM and 2:1 hexane/EtOAc. The mixture was then concentratedto give the aldehyde as a light yellow oil (28.5 g, 99%).

To a solution of methyl diethylphosphonoacetate (24.8 g, 117.8 mmol) inTHF (400 mL) was add LDA (2.0 N, 58.9 mL, 117.8 mmol) at 0° C. After 30min, a solution of the aldehyde from the previous step (28.5 g, 98.2mmol) in THF (100 mL) was added, and the mixture was stirred at roomtemperature for two days and was then brought to reflux temperatureovernight. The solvent was removed by rotary evaporation. The mixturewas quenched with saturated NH₄Cl and extracted with EtOAc. The combinedorganic layers were washed with brine, dried, filtered, concentrated,and purified by medium pressure-liquid chromatography to give theunsaturated ester (31.3 g, 90.7%).

To a solution of the unsaturated ester (20 g, 56.9 mmol) in MeOH (200mL) was added Pd/C (10%, 6.05 g), and the suspension was placed on ashaker under a hydrogen gas atmosphere (50 psi) overnight. The solid wasfiltered and washed with MeOH, and solvents were removed to give theproduct (19.3 g, 96%).

To a solution of the ester (2.9 g, 8.2 mmol) in dry THF (100 mL) wasadded MeLi (1.4 N in THF, 29.3 mL, 41.0 mmol) at −78° C. The mixture wasstirred at −78° C. for 3 h and quenched with HCl (4.0 N in dioxane, 10.0mL). The solvent was removed and the residue was washed with ether. Theether solution was concentrated to give the product (2.85 g, 98%) as anoil.

To a solution of HCl in dioxane (4 N, 14.1 mL, 56.6 mmol) was added theN-Boc-protected alcohol (2.0 g, 5.66 mmol) at room temperature. Themixture was stirred for 1 h and then the solution was evaporated to giveIntermediate 15 (1.34 g, 81.7%) as a white solid.

Piperidine Intermediate 16:

A dry flask was charged with NaH (60% in oil, 960 mg, 24 mmol) andanhydrous THF (40 mL). Added the alcohol starting material (5.95 g, 20mmol) in dry THF (20 ml) through a two-ended needle under nitrogenatmosphere. Stirred at room temperature for about 60 min or untilbubbling ceased, then added ethyl 2-bromoisopropionate (3.12 ml, 24mmol). The mixture was stirred at room temperature overnight undernitrogen atmosphere. Quenched the reaction by adding the reactionmixture in portions to EtOAc (200 ml)/ice water (50 ml) with stirring.Transferred the mixture to a separatory funnel and added 1N HCl (30 ml).Extracted the aqueous solution with EtOAc (3×150 ml). Combined theorganic phases which were dried over MgSO₄. Concentrated in vacuo andpurified by flash column chromatography on silica gel using 20% EtOAc inhexane as eluent to give the desired product (1.0 g, 13%). LC-MS:M+1=398.5.

To the stirred solution of the Boc-derivative (1.0 g, 2.5 mmol) in dryTHF (50 ml) was added LDA (1.5 M in cyclohexane, 2.0 ml, 3 mmol)dropwise at −78° C. The mixture was stirred at −78° C. for 30 min, thenMeI (784 μl, 12.5 mmol) was added. Slowly warmed up to room temperatureand stirred at room temperature overnight. Quenched the reaction byadding the reaction mixture in portions to EtOAc (200 ml)/ice water (50ml) with stirring. Transferred the mixture to a separatory funnel andadded 1N HCl (30 ml). Extracted the aqueous solution with EtOAc (3×150ml). Combined the organic phases and dried over MgSO₄. Concentrated invacuo and purified by flash column chromatography on silica gel using20% EtOAc in hexane as eluent to give the desired product as a thick oil(681.8 mg). LC-MS: M+1=412.

¹H NMR (400 MHz, CDCl₃): δ 4.13 (q, J=7.2, 2H), 3.52 (br, 2H), 3.25 (s,2H), 3.18–3.12 (m, 2H), 1.75–1.61 (m, 5H), 1.53–1.388 (m, 4H), 1.42 (s,9H), 1.35 (s, 6H), 1.27 (t, J=7.2, 3H), 1.10 (m, 6H).

Dissolved the above resulting compound in 4N HCl in dioxane (20 ml).Stirred at room temperature for about 60 min. Evaporated to dryness togive Intermediate 16 as a white solid (541 mg). LC-MS: M+1=312.

Piperidine Intermediate 17:

To the stirred solution of N-Cbz-4-cyclohexyl-piperidine-4-carboxylicacid (1.0 g, 2.9 mmol) in DCM (20 ml) was added oxalyl chloride (2.0M inDCM, 1.6 ml, 3.19 mmol) dropwise. Then added 3 drops of DMF. Stirred atroom temperature for 1 hour and then evaporated to give the desiredproduct. The crude mixture was used in the next step without furtherpurification.

To the stirred solution of the acid chloride (2.9 mmol) in1,2-dichloroethane (30 ml) was added α-methylalanine methyl ester (446mg, 2.9 mmol) and DIEA (1.01 ml, 5.8 mmol). Stirred at 75° C. for 1hour, and then at 60° C. overnight. Cooled to room temperature anddiluted the mixture with DCM. Washed with 1N HCl, satd. NaHCO₃ and thensatd. NaCl. Dried over Na₂SO₄ and concentrated in vacuo to give thecrude desired product (1.2 g). LC-MS: 445 (M+1).

Dissolved intermediate from previous step (1.2 g, 2.7 mmol) in ethanol(50 ml). Added Pd-C (10%, 200 mg) and stirred at room temperature in thepresence of hydrogen gas for two hours. Filtered off the catalyst, andconcentrated in vacuo to give Intermediate 17 (663 mg). LC-MS: 312(M+1).

Piperidine Intermediate 18:

To a solution of the enone (6 mmol, 0.7 mL) in MeOH (20 mL) at 0° C. wasadded NaBH₄ (3 mmol, 113 mg). The reaction was stirred at room temp for1 hr. Volatiles were removed and the residue partitioned between CH₂Cl₂and 0.5M HCl. Organic phase was dried over MgSO₄ and concentrated toafford a clear colorless oil which was used in the next step withoutfurther purification.

A solution of the acid (6 mmol, 1.38 g), EDC (12 mmol, 2.3 g), DMAP(ca.50 mg) and enol (ca. 6 mmol) in CH₂Cl₂ (25 mL) was stirred at roomtemp for 72 hours. Reaction mixture was poured into EtOAc (200 mL) andwashed successively with 0.5M HCl, 1M NaOH, H₂O and brine, dried overNa₂SO₄ and concentrated. Chromatography over silica gel eluting with 500mL of 5–10% EtOAc/hexane afforded a clear colorless oil (1.9 g).

To a solution of LDA (2M in THF) (4.38 mmol, 2.2 mL) in THF (10 mL) at−78° C. was added the ester from the previous step (3.98 mmol, 1.3 g) inTHF (2 mL) followed 30 min later by TMSCI (4.38 mmol, 0.6 mL). Resultantsolution was allowed to warm to room temperature and then heated atreflux for 16 hr. After cooling to room temp, 2M HCl (5 mL) was addedand stirring continued for 5 min. Resultant solution was partitionedbetween Et₂O (40 mL) and 2M HCl. The organic phase was washed with H₂Oand brine, dried over Na₂SO₄ and concentrated. Chromatography oversilica eluting with 20–30% EtOAc/hexane afforded the desired acid as anoff-white solid (653 mg).

To a solution of the acid from the previous step (1.46 mmol, 474 mg) inCH₂Cl₂ (5 mL) at 0° C. was added oxalyl chloride (2M in CH₂Cl₂) (1.61mmol, 0.81 mL) and DMF (0.05 mL) and the reaction stirred at 0° C. for 1hr. Volatiles were removed, azeotroping with toluene and finally underhigh vacuum for 3 hr to afford the acid chloride. The acid chloride wasdissolved in t-butylamine (5 mL) and the resultant cloudy solution wasstirred at room temperature overnight. The reaction mixture wasconcentrated to afford a yellow solid. Chromatography over silica geleluting with 50 mL of 5% then 100 mL of 10–20% EtOAc/hexane afforded thedesired tert-butyl amide as a white solid (282 mg).

A suspension of Pd (10% on activated charcoal) (10 mol %, 79 mg) in asolution of the N-Boc derivative from the previous step (0.75 mmol, 282mg) in MeOH containing 4M HCl (4M in dioxane) (1.5 mmol, 0.37 mL) wasshaken under 45 psi of hydrogen gas for 60 hours. After work-up, thehydrochloride salt was used without further purification in the peptidecoupling reaction.

Piperidine Intermediate 19:

To a solution of the acid (10 mmol, 2.29 g) in CH₂Cl₂ (40 mL) at roomtemp was added EDC (20 mmol, 3.8 g) and DMAP (ca.50 mg) followed by3-methyl-2-buten-1-ol (15 mmol, 1.52 mL). Resultant solution was stirredat room temp overnight. Reaction mixture was poured into EtOAc (200 mL)and washed successively with 0.5M HCl, 1M NaOH, H₂O and brine, driedover Na₂SO₄ and concentrated. Chromatography over silica gel elutingwith 500 mL of 5% then 250 mL of 10% EtOAc/hexane afforded the ester asa clear colorless oil (2.97 g).

To a solution of LDA (2M in THF) (7.46 mmol, 3.73 mL) in THF (15 mL) at−78° C. was added the ester from the previous step (6.78 mmol, 2.02 g)in THF (3 mL) followed 30 min later by TMSCl (7.46 mmol, 0.95 mL).Resultant solution was allowed to warm to room temp and heated at refluxfor 24 hr. After cooling to room temp, 2M HCl (5 mL) was added andstirring continued for 5 min. Resultant solution was partitioned betweenEt₂O (40 mL) and 2M HCl. The organic phase was washed with H₂O andbrine, dried over Na₂SO₄ and concentrated. Chromatography over silicaeluting with 10–20% EtOAc/hexane afforded the desired acid as a whitesolid (1.23 g).

To a solution of the acid from the previous step (4.14 mmol, 1.23 g) inCH₂Cl₂ (10 mL) at 0° C. was added oxalyl chloride (2M in CH₂Cl₂) (4.55mmol, 2.27 mL) and DMF (0.15 mL) and the reaction stirred at 0° C. for 1hr. Volatiles were removed, azeotroping with toluene and finally underhigh vacuum for 3 hr to afford the acid chloride. The acid chloride wasdissolved in t-butylamine (10 mL) and the resultant cloudy solution wasleft to stir at room temperature overnight. The reaction mixture wasconcentrated and partitioned between CH₂Cl₂ and 2M HCl. Organics weredried over Na₂SO₄ and concentrated. Chromatography over silica geleluting with 10–30% EtOAc/hexane afforded a white solid (1.07 g).

A suspension of Pd (10% on activated charcoal) (10 mol %, 322 mg) in asolution of the compound from the previous step (3.03 mmol, 1.07 g) inMeOH (60 mL) containing 4M HCl in dioxane (6.06 mmol, 1.5 mL) was shakenunder 45 psi of hydrogen gas for 5 hr. Reaction was filtered through ashort pad of celite and concentrated. Residue was dissolved in EtOAc (20mL) and HCl (4M in dioxane) (20 mL). Resultant solution was left to stirat room temp for 1 hr. Volatiles were removed and the residueprecipitated from a CH₂Cl₂ solution with Et₂O/hexane to affordIntermediate 19 as a white solid.

Piperidine Intermediate 20:

To a solution of CrO₃ (15.8 mmol, 1.59 g) in dry CH₂Cl₂ (20 mL) at −20°C. was added 3,5-dimethylpyrazole (15.8 mmol, 1.52 mg) in one portion.The resultant solution was stirred at −20° C. for 15 min before theaddition of the cyclohexene intermediate (0.79 mmol, 289 mg) in CH₂Cl₂(2.5 mL) over 3 min. The reaction mixture was warmed to −15° C. andstirred for a further 5 hr. 5N NaOH (51.5 mmol, 10.3 mL) was added andthe emulsion stirred at 0° C. for 1 hr then at rt overnight. Aqueousphase was extracted with CH₂Cl₂, and the combined organics were washedwith 1N HCl, water, satd NaHCO₃ and brine, dried over Na₂SO₄ andconcentrated. Chromatography over silica gel eluting with 50 mL of 0,2.5, 5, and 10% EtOAc/hexane afforded the cyclohexenone as a white solid(135 mg).

A suspension of Pd (10% on activated charcoal) (20 mol %, 76 mg) in asolution of the cyclohexenone (0.36 mmol, 135 mg) in MeOH was shakenunder 45 psi of hydrogen gas for 60 hr. The reaction mixture wasfiltered through a short pad of celite and concentrated to afford aclear colorless gum. Chromatography over silica gel eluting with 50 mLof 0, 2.5, 5, 10, and 20% Me₂CO/CH₂Cl₂ afforded the cyclohexanone as awhite solid (111 mg).

To a solution of the cyclohexanone (0.29 mmol, 111 mg) in CH₂Cl₂ wasadded (diethylamino)sulfur trifluoride (0.73 mmol, 0.1 mL). Resultantsolution was left to stir at room temp for 24 hours. Reaction mixturewas poured into saturated NaHCO₃. Organic phase was washed with NaHCO₃,dried over Na₂SO₄ and concentrated. Chromatography over silica geleluting with 10–30% EtOAc/hexane afforded the difluorocyclohexaneintermediate as a white solid (84 mg)

A solution of the difluorocyclohexane intermediate from the previousstep (0.2 mmol, 80 mg) in CH₂Cl₂ and TFA was stirred at room temp for 1hr. Volatiles were removed and the residue partitioned between NaOH andEtOAc. Organic phase was dried over Na₂SO₄ and concentrated to giveIntermediate 20.

Piperidine Intermediate 21:

To a suspension of Reike Mg (5 g/200 mL THF) (6 mmol, 6 mL) at 0° C. wasadded a solution of 4-methyl-1-bromocyclohexane (4 mmol, 708 mg) in THF(4 mL) over a period of about 5 min. The resultant slurry was stirred atroom temp for 5 min then cooled to −20° C. A solution of theCbz-piperidine derivative (1 mmol, 276 mg) in THF (10 mL) was thenadded. The reaction was stirred at −20° C. for 15 min then poured intoice-cold 50% H₂SO₄ (25 mL) and stirred for a further 30 min. Theemulsion was poured into H₂O (100 mL) and extracted with CH₂Cl₂ (2×25mL). The combined organic phases were dried over Na₂SO₄ and concentratedto afford a green oil. To a solution of this oil in DMSO (2 mL) wasadded NaNO₂ (3 mmol, 207 mg) and AcOH (10 mmol, 0.6 mL). The resultantorange solution was stirred at 40° C. for 24 hr. After cooling to roomtemperature, 1N HCl (2.5 mL) was added and stirring continued for afurther 15 min. The mixture was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated.Chromatography over silica gel eluting with 100 mL of 10% and 50 mL of20–30% EtOAc/hexane afforded the desired acid as an off-white solid (100mg).

To a solution of the acid (0.42 mmol, 151 mg) in CH₂Cl₂ (2.5 mL) at 0°C. was added oxalyl chloride (2M in CH₂Cl₂) (0.46 mmol, 0.23 mL) and DMF(4 drops) and the reaction stirred at 0° C. for 1 hr. Volatiles wereremoved, azeotroping with toluene and finally under high vacuum for 3 hrto afford the acid chloride. The acid chloride was dissolved in CH₂Cl₂(2.5 mL) and cooled to 0° C. t-Butylamine (1.26 mmol, 0.13 mL) was addedand the resultant cloudy solution was left to stir at room temperatureovernight. The reaction mixture was poured into CH₂Cl₂ (ca. 3 mL) andwashed with brine, dried over Na₂SO₄ and concentrated. Chromatographyover silica gel eluting with 250 mL of 20, 25, 30, and 40% EtOAc/hexaneafforded the Cbz-protected t-butyl amide as a white foam (174 mg). Amixture of the Cbz-protected t-butyl amide (0.1 mmol, 174 mg) andcatalytic Pd (10% on activated C) (20 mg) in methanol was stirred underan atmosphere of hydrogen gas at room temp for 1 hr. The solution wasfiltered through a short pad of celite and concentrated to giveIntermediate 21.

Piperidine Intermediate 22:

A solution of the amine (400 mg, 1.42 mmol), cyclopropylsulfonylchloride (600 mg, 4.26 mmol), DIEA (1.47 g, 11.36 mmol) and DMAP (100mg, 0.8 mmol) in toluene (50 mL) was heated to reflux overnight. Asolution of NaOH (5N, 10 mL) was added and allowed the reaction toreflux for an additional 4 h. The reaction mixture was cooled to rt anddiluted with EtOAc (200 mL). The combined organics were washed with 0.5NHCl, satd NaHCO₃, and brine, dried over Na₂SO₄ and concentrated.Chromatography over silica gel eluting with 50 mL of 10, 20, 15, 25, 40,and 50% EtOAc/hexane afforded the Boc-protected intermediate as a whitesolid (615 mg). A solution of this intermediate in CH₂Cl₂ (4 mL) and HCl(4M in dioxane) (4 mL) was stirred at room temp for 1 hr. Volatiles wereremoved and the product precipitated from a CH₂Cl₂ solution withEt₂O/hexane to give Intermediate 22 (615 mg).

Piperidine Intermediate 23:

To a solution of the ester (2.36 g, 9.17 mmol) in THF (50 mL) at −78° C.was added LDA (1.5M in 1) (6.72 mL, 10.09 mmol) and followed 45 minlater by cyclopropylmethyl bromide (1.49 g, 11.0 mmol) in THF (10 mL).Resultant solution was allowed to warm to room temp overnight. Resultantsolution was quenched with sat. NH₄Cl and partitioned between EtOAc (40mL) and 0.5M HCl. The organic phase was washed with H₂O and brine, driedover Na₂SO₄ and concentrated. Chromatography over silica gel elutingwith 5% EtOAc/hexane afforded the alkylated product (2.76 g).

A solution of intermediate from the previous step (2.76 g, 8.86 mmol)and LiOH (1.1 g, 44.3 mmol) in MeOH/H₂O (70 mL) was heated to refluxovernight. More MeOH was added to the reaction mixture to make thesolution homogeneous. The reaction mixture was concentrated to about 10mL and acidified with 2N HCl to pH about 2. The aqueous solution wasextracted with EtOAc (3×100 mL). The organics were washed successivelywith H₂O and brine, dried over Na₂SO₄ and concentrated. Chromatographyover silica gel eluting with 20–70% EtOAc/hexane afforded theBoc-protected acid as a white solid (1.69 g). To a solution of the acid(2.5 g, 8.82 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added oxalyl chloride(2M in CH₂Cl₂) (4.85 mL, 9.70 mmol) and DMF (0.05 mL) and the reactionstirred at 0° C. for 1 hr. Volatiles were removed, azeotroping withtoluene and finally under high vacuum for 3 hr to afford the acidchloride. The acid chloride was dissolved in t-butylamine (2.8 mL), andthe resultant cloudy solution was left to stir at room temp overnight.The reaction mixture was concentrated and partitioned between CH₂Cl₂ and2M HCl. Organics were dried over Na₂SO₄ and concentrated. A solution ofthe Boc-protected amide in CH₂Cl₂ (4 mL) and 4.0 M HCl/dioxane (4 mL)was stirred at room temp for 1 hr. Volatiles were removed andIntermediate 23 was precipitated from a CH₂Cl₂ solution with Et₂O/hexane(1.9 g).

Piperidine Intermediate 24:

This intermediate was prepared in the same manner as Intermediate 23 butusing cyclobutylmethyl bromide in place of cyclopropylmethyl bromide inthe alkylation step.

Piperidine Intermediate 25:

To a solution of the acid (600 mg, 2.117 mmol) in THF (5 mL) at 0° C.was added BH₃.Me₂S (10 M in THF) (0.85 mL, 8.47 mmol) and the solutionwas left to stir at room temperature for 3 h. The reaction mixture wasthen cooled to 0° C., and H₂O₂ (30% aqueous, 2.5 mL) was added dropwiseand then 1M NaOH (10 mL). The resultant solution was stirred for 10 minat 0° C. and then a further 30 min at rt. The reaction mixture waspoured into EtOAc (100 mL), and washed successively with water, sat.NH₄Cl, saturated NaHCO₃, and brine, dried over Na₂SO₄ and concentrated.Chromatography over silica gel eluting with 40% EtOAc/hexane affordedthe alcohol intermediate (611 mg). To a solution of the alcohol (611 mg,2.268 mmol) and Et₃N (0.63 mL, 4.5 mmol) in CH₂Cl₂ (5 mL) at 0° C. wasadded methanesulfonyl chloride (10 M in THF) (0.35 mL, 4.53 mmol) at 0°C. and the solution was left to stir at room temp 45 min. The reactionwas concentrated and was poured into water (100 mL), and extracted withEtOAc (3×100 mL). The organics were dried over Na₂SO₄ and concentrated.Chromatography over silica gel eluting with 5–30% EtOAc/hexane affordedthe mesylate as a solid. To a solution of the mesylate (596 mg, 1.7mmol) in DMF (5 mL) at rt was added sodium isopropylsulfide (842 mg,8.57 mmol) and the solution was left to stir at room temp overnight. Thereaction was concentrated and was poured into water (100 mL), andextracted with EtOAc (3×100 mL). The organics were dried over Na₂SO₄ andconcentrated. Chromatography over silica gel eluting with 5–30%EtOAc/hexane afforded a solid. A solution of the Boc-protected isopropylsulfide in CH₂Cl₂ (4 mL) and 4.0 M HCl/dioxane (4 mL) was stirred atroom temp for 1 hr. Volatiles were removed and Intermediate 25 wasprecipitated from a CH₂Cl₂ solution with Et₂O/hexane (400 mg).

Piperidine Intermediate 26:

To a solution of the amino alcohol (177 mg, 0.48 mmol), NaOH (192 mg,4.8 mmol) in CHCl₃ (5 mL) and water (2 mL) at 0° C. was added dropwise asolution of BrCH₂COBr (263 mg, 1.3 mmol) in CHCl₃ (1 mL) over a periodof 5 min., and the solution was left to stir at 0° C. for 1 h and thenat rt overnight. The reaction was concentrated and was poured into water(100 mL), and extracted with EtOAc (3×100 mL). The organics were washedsuccessively with water, 1N HCl and brine and dried over Na₂SO₄ andconcentrated. Chromatography over silica gel eluting with 25%EtOAc/hexane afforded a solid. A solution of this solid in CH₂Cl₂ (4 mL)and 4.0 M HCl/dioxane (4 mL) was stirred at room temp for 1 hr.Volatiles were removed and Intermediate 26 precipitated from a CH₂Cl₂solution with Et₂O/hexane (100 mg).

The following Examples are provided to illustrate the invention and arenot to be construed as limiting the scope of the invention in anymanner.

EXAMPLE 1

Step A:

To a solution of compound 1-1 (10 g, 41 mmol, Maybridge, BTBG 0121) in50 mL of methanol was added palladium on carbon (0.41 g). The mixturewas stirred at r.t. under hydrogen gas (1 atmosphere) overnight. Thesolid was filtered and washed with methanol. The filtrates wereconcentrated to give 1-1 as colorless oil (6.3 g).

ESI-MS: Calcd for C₉H₁₃NO₂: 155; Found: 156 (M⁺+1).

Step B:

To a solution of compound 1-1′ (6.3 g, 41 mmol) in 50 mL of THF wereadded TEA (6.8 mL, 49 mmol) and benzyl chlorofomate (7.6 g, 45 mmol).The reaction mixture was stirred at r.t. overnight. The reaction mixturewas diluted with ethyl acetate and washed with 1N HCl and brine, driedover MgSO₄, filtered and concentrated to give compound 1-2 as an thickoil (11 g).

ESI-MS: Calcd. for C₁₆H₁₉NO₄: 289; Found: 290 (M⁺+1).

Step C:

To a solution of compound 1-2 (11 g, 39 mmol) in 80 mL of THF was addeda solution of lithium hydroxide (2.8 g, 119 mmol) in 20 mL of H₂O. Thereaction mixture was stirred at r.t. overnight. The reaction mixture wasconcentrated and H₂O was added and then acidified by adding aqueous 1 NHCl solution until a pH of about 4 was achieved. The solution wasextracted with EtOAc, and the combined organic extracts were washed withbrine, dried over MgSO₄, filtered, and concentrated to give compound 1-3as an off-white solid (7.2 g).

ESI-MS: Calcd. for C₁₅H₁₇NO₄: 275; Found: 276 (M⁺+1).

Step D:

Acid 1-3 (0.59 g, 2.1 mmol) was dissolved in 10 mL of DMF, and then the4-F-D-Phe-4-cyclohexyl-piperidine-4-carboxylic acid tert-butyl amide(1.0 g, 2.1 mmol), DIEA (0.83 g, 6.4 mmol), EDC (0.49 g, 2.6 mmol), andHOBt (0.35 g, 2.6 mmol) were added. The resulting mixture was stirred atr.t. overnight, and then diluted with ethyl acetate, and washed with 1NHCl solution, saturated NaHCO₃ solution, and brine. The organic layerwas dried over MgSO₄, filtered, and concentrated. The isomers wereseparated by medium-pressure liquid chromatography (1:1 ethylacetate-methylene chloride as eluant) to give 1-4A (diastereomer 1, 0.52g) and 1-4B (diastereomer 2, 0.51 gm).

ESI-MS (1-4A diastereomer 1): Calcd. for C₄₀H₅₃N₄O₅F: 688; Found: 689(M⁺+1).

ESI-MS (1-4B diastereomer 2): Calcd. for C₄₀H₅₃N₄O₅F: 688; Found: 689(M⁺+1).

Step E:

To a solution of compound 1-4A (diastereomer 1, 0.52 g, 0.76 mmol) in 10mL of methanol was added palladium-on-carbon (0.01 g). The mixture wasstirred at r.t. under hydrogen gas (1 atmosphere) overnight. The solidwas filtered and washed with methanol. The filtrates were concentratedto give 1-4A (diastereomer 1, 0.41 g).

ESI-MS: Calcd for C₃₂H₄₇N₄O₃F: 554; Found: 555 (M⁺+1).

To a solution of compound 1-4B (diastereomer 2, 0.51 g, 0.74 mmol) in 10mL of methanol was added Palladium on carbon (0.01 g). The mixture wasstirred at r.t. under hydrogen gas (1 atmosphere) overnight. The solidwas filtered and washed with methanol. The filtrates were concentratedto give 1-4B (diastereomer 2, 0.40 g).

ESI-MS: Calcd for C₃₂H₄₇N₄O₃F: 554; Found: 555 (M⁺+1).

Step F:

To a solution of compound 1-4A (diastereomer 1, 0.11 g, 0.20 mmol) in 5mL of methanol was added formaldehyde (0.20 mL, 37% in water, 2.0 mmol).After the mixture was stirred for 30 min, a solution of NaCNBH₃ (1.0 mL,1.0 M, 1.0 mmol) was added. The mixture was then stirred at r.t.overnight and solvents were removed under reduced pressure. The residuewas quenched with sat'd NaHCO₃ and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to give 1-5A (diastereomer 1, 0.097 g).

ESI-MS: Calcd for C₃₃H₄₉N₄O₃F: 568; Found: 569 (M⁺+1).

To a solution of compound 1-4B (diastereomer 2, 0.11 g, 0.20 mmol) in 5mL of methanol was added formaldehyde (0.20 mL, 37% in water, 2.0 mmol).After the mixture was stirred for 30 min, a solution of NaCNBH₃ (1.0 mL,1.0 M, 1.0 mmol) was added. The mixture was then stirred at r.t.overnight and solvents were removed under reduced pressure. The residuewas quenched with sat'd NaHCO₃ and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered, andconcentrated to give 1-5B (diastereomer 2, 0.097 g).

ESI-MS: Calcd for C₃₃H₄₉N₄O₃F: 568; Found: 569 (M⁺+1).

The following Examples shown in Table 1 having the indicated Rstereochemistry at the stereogenic center marked with an * and theindicated anti stereochemistry at the stereogenic center marked with an** relative to the [2.2.1]-bicycle ring nitrogen were prepared in asimilar fashion as Example 1 following the methodologies shown inSchemes A and B.

TABLE 1

Diastereomer with antistereo- Mass Ex. X R⁶ chem at ** R⁵ spectrum 2

Cl d₁ H 544 (M⁺ + 1) 3

Cl d₂ H 544 (M⁺ + 1) 4

F d₁ + d₂ H 528 (M⁺ + 1) 5

F d₁ + d₂ iPr 570 (M⁺ + 1) 6

F d₁ H 555 (M⁺ + 1) 7

F d₂ H 555 (M⁺ + 1) 8

F d₁ iPr 597 (M⁺ + 1) 9

F d₂ iPr 597 (M⁺ + 1)

EXAMPLE 10

Step A:

To a solution of compound 2-1 (1.0 g, 3.6 mmol) [for preparation of 2-1,see Tetrahedron, 48: 8751 (1992) and J. Med. Chem., 33: 2690 (1996)] in10 mL of methanol was added palladium-on-carbon (0.035 g). The mixturewas stirred at r.t. under hydrogen gas (1 atmosphere) overnight. Thesolid was filtered and washed with methanol. The filtrates wereconcentrated to give 2-2 as a colorless oil (0.95 g).

ESI-MS: Calcd for C₁₄H₂₃NO₄: 269; Found: 270 (M⁺+1).

Step B:

To a solution of compound 2-2 (0.95 g, 3.5 mmol) in 15 mL of THF wasadded a solution of lithium hydroxide (0.5 g, 23 mmol) in 5 mL of H₂O.The reaction mixture was stirred at r.t. overnight. The reaction mixturewas concentrated and H₂O was added and then acidified by adding aqueous1 N HCl solution until a pH of about 4 was achieved. The solution wasextracted with EtOAc, and the combined organic extracts were washed withbrine, dried over MgSO₄, filtered, and concentrated to give compound 2-3as a white solid (0.78 g).

ESI-MS: Calcd. for C₁₃H₂₁NO₄: 255; Found: 256 (M⁺+1).

Step C:

Acid 2-3 (0.55 g, 2.1 mmol) was dissolved in 30 mL of methylenechloride, and then the 4-F-D-Phe-4-cyclohexyl-piperidine-4-carboxylicacid tert-butyl amide (1.0 g, 2.1 mmol), DIEA (0.37 mL, 2.1 mmol), EDC(0.82 g, 4.2 mmol), and HOBt (0.29 g, 2.1 mmol) were added. Theresulting mixture was stirred at r.t. overnight, and then diluted withmethylene chloride, and washed with 1N HCl solution, saturated NaHCO₃solution, and brine. The organic layer was dried over MgSO₄, filtered,and concentrated. The isomers were purified by flash chromatography onsilica gel (2:3 EtOAc-hexane) to give 2-4A (diastereomer 1, 0.55 g) and2-4B (diastereomer 2, 0.62 gm).

ESI-MS (1-4A): Calcd. for C₃₈H₅₇N₄O₅F: 668; Found: 669 (M⁺+1).

ESI-MS (1-4B): Calcd. for C₃₈H₅₇N₄O₅F: 668; Found: 669 (M⁺+1).

Step D:

Compound 2-4A (diastereomer 1, 0.52 g, 0.78 mmol) was dissolved in 10 mLof 4 N HCl in dioxane. This solution was stirred at r.t. for 60 min, andthen concentrated to give 2-4A as a white solid (diastereomer 1, 0.48g).

ESI-MS: Calcd for C₃₃H₄₉N₄O₃F: 568; Found: 569 (M⁺+1).

Compound 2-4B (diastereomer 2, 0.43 g, 0.64 mmol) was dissolved in 10 mLof 4 N HCl in dioxane. This solution was stirred at r.t. for 60 min, andthen concentrated to give 2-4B as a white solid (diastereomer 2, 0.39g).

ESI-MS: Calcd for C₃₃H₄₉N₄O₃F: 568; Found: 569 (M⁺+1).

Step E:

To a solution of compound 2-4A (diastereomer 1, 0.11 g, 0.18 mmol) in 2mL of methylene chloride was added formaldehyde (0.15 mL, 37% in water,1.8 mmol), DIEA (0.032 mL, 0.18 mmol), and molecular sieves (700 mg, 4Apowder). After the mixture was stirred for 5 min, Na(OAc)₃BH (0.37 g,1.8 mmol) was added and the mixture was then stirred at r.t. overnight.The mixture was diluted with methylene chloride, washed with saturatedNaHCO₃, dried over NaSO₄, filtered, and concentrated to give 2-5A(diastereomer 1, 0.11 g).

ESI-MS: Calcd for C₃₄H₅₁N₄O₃F: 582; Found: 583 (M⁺+1).

To a solution of compound 2-4B (diastereomer 2, 0.10 g, 0.17 mmol) in 2mL of methylene chloride was added formaldehyde (0.13 mL, 37% in water,1.7 mmol), D]EA (0.029 mL, 0.17 mmol), and molecular sieves (700 mg, 4Apowder). After the mixture was stirred for 5 min, Na(OAc)₃BH (0.35 g,1.7 mmol) was added and the mixture was then stirred at r.t. overnight.The mixture was diluted with methylene chloride, washed with sat'dNaHCO₃, dried over NaSO₄, filtered, and concentrated to give 2-5B(diastereomer 2, 0.085 g).

ESI-MS: Calcd for C₃₄H₅₁N₄O₃F: 582; Found: 583 (M⁺+1).

The following Examples shown in Table 2 having the indicated Rstereochemistry at the stereogenic center marked with an * and theindicated anti stereochemistry at the stereogenic center marked with an** relative to the [2.2.2]-bicycle ring nitrogen were prepared in asimilar fashion as Example 10 following the methodologies shown inSchemes A and B.

TABLE 2

Diastereomer with Mass Ex. X R⁶ anti-stereochem at ** R⁵ spectrum 11

F d₁ + d₂ H 542 (M⁺ + 1) 12

F d₂ Me 556 (M⁺ + 1) 13

F d₁ + d₂ iPr 584 (M⁺ + 1) 14

F d₁ + d₂ cyclobutyl 596 (M⁺ + 1) 15

F d₁ + d₂

613 (M⁺ + 1) 16

F d₁ —CH₂CO₂H 600 (M⁺ + 1) 17

F d₁ —CH₂CONH₂ 599 (M⁺ + 1) 18

F d₁

763 (M⁺ + 1) 19

F d₁

636 (M⁺ + 1) 20

F d₁ —COCH₂NH₂ 599 (M⁺ + 1) 21

F d₁ + d₂ H 569 (M⁺ + 1) 22

Cl d₁ + d₂ Me 583 (M⁺ + 1) 23

Cl d₁ + d₂ iPr 611 (M⁺ + 1) 24

F d₁ + d₂ cyclobutyl 623 (M⁺ + 1) 25

F d₁ 2,2-difluoroethyl 633 (M⁺ + 1) 26

F d1

640 (M⁺ + 1) 27

Cl d₁ + d₂ H 586 (M⁺ + 1) 28

Cl d₁ + d₂ H 544 (M⁺ + 1) 29

F d₁ + d₂ H 572 (M⁺ + 1) 30

Cl d₁ + d₂ H 569 (M⁺ + 1) 31

F d₁ + d₂ iPr 611 (M⁺ + 1) 32

F d₁ + d₂ H 614 (M⁺ + 1) 33

F d₁ Me 628 (M⁺ + 1) 34

F d₁ + d₂ H 583 (M⁺ + 1) 35

F d₁ + d₂ cyclobutyl 637 (M⁺ + 1) 36

F d₁ + d₂ Me 583 (M⁺ + 1) 37

F d₁ + d₂ Me 581 (M⁺ + 1)Biological Assays:A. Binding Assay. The membrane binding assay was used to identifycompetitive inhibitors of ¹²⁵I-NDP-alpha-MSH binding to cloned humanMCRs expressed in L- or CHO-cells.

Cell lines expressing melanocortin receptors were grown in T-180 flaskscontaining selective medium of the composition: 1 L Dulbecco's modifiedEagles Medium (DMEM) with 4.5 g L-glucose, 25 mM Hepes, without sodiumpyruvate, (Gibco/BR1); 100 ml 10% heat-inactivated fetal bovine serum(Sigma); 10 ml 10,000 unit/ml penicillin & 10,000 ug/ml streptomycin(Gibco/BR1); 10 ml 200 mM L-glutamine (Gibco/BR1); 1 mg/ml Geneticin(G418) (Gibco/BR1). The cells were grown at 37° C. with CO₂ and humiditycontrol until the desired cell density and cell number was obtained.

The medium was poured off and 10 mls/monolayer of enzyme-freedissociation media (Specialty Media Inc.) was added. The cells wereincubated at 37° C. for 10 minutes or until cells sloughed off whenflask was banged against hand.

The cells were harvested into 200 ml centrifuge tubes and spun at 1000rpm, 4° C., for 10 min. The supernatant was discarded and the cells wereresuspended in 5 mls/monolayer membrane preparation buffer having thecomposition: 10 mM Tris pH 7.2–7.4; 4 ug/ml Leupeptin (Sigma); 10 uMPhosphoramidon (Boehringer Mannheim); 40 ug/ml Bacitracin (Sigma); 5ug/ml Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cellswere homogenized with motor-driven dounce (Talboy setting 40), using 10strokes and the homogenate centrifuged at 6,000 rpm, 4° C., for 15minutes.

The pellets were resuspended in 0.2 mls/monolayer membrane prep bufferand aliquots were placed in tubes (500–1000 ul/tube) and quick frozen inliquid nitrogen and then stored at −80° C.

Test compounds or unlabelled NDP-α-MSH was added to 100 μL of membranebinding buffer to a final concentration of 1 μM. The membrane bindingbuffer had the composition: 50 mM Tris pH 7.2; 2 mM CaCl2; 1 mM MgCl2; 5mM KCl; 0.2% BSA; 4 ug/ml Leupeptin (SIGMA); 10 uM Phosphoramidon(Boehringer Mannheim); 40 ug/ml Bacitracin (SIGMA); 5 ug/ml Aprotinin(SIGMA); and 10 mM Pefabloc (Boehringer Mannheim). One hundred μl ofmembrane binding buffer containing 10–40 ug membrane protein was added,followed by 100 μM 125I-NDP-α-MSH to final concentration of 100 pM. Theresulting mixture was vortexed briefly and incubated for 90–120 min atroom temp while shaking.

The mixture was filtered with Packard Microplate 196 filter apparatususing Packard Unifilter 96-well GF/C filter with 0.1% polyethyleneimine(Sigma). The filter was washed (5 times with a total of 10 ml per well)with room temperature of filter wash having the composition: 50 mMTris-HCl pH 7.2 and 20 mM NaCl. The filter was dried, and the bottomsealed and 50 ul of Packard Microscint-20 was added to each well. Thetop was sealed and the radioactivity quantitated in a Packard TopcountMicroplate Scintillation counter.

B. Functional assay. Functional cell based assays were developed todiscriminate melanocortin receptor agonists from antagonists.

Cells (for example, CHO- or L-cells or other eukaryotic cells)expressing a human melanocortin receptor (see e.g. Yang-Y K; Ollmann-MM; Wilson-B D; Dickinson-C; Yamada-T; Barsh-G S; Gantz-I;Mol-Endocrinol. 1997 March; 11(3): 274–80) were dissociated from tissueculture flasks by rinsing with Ca and Mg free phosphate buffered saline(14190-136, Life Technologies, Gaithersburg, Md.) and detached following5 minutes incubation at 37° C. with enzyme free dissociation buffer(S-014-B, Specialty Media, Lavellette, N.J.). Cells were collected bycentrifugation and resuspended in Earle's Balanced Salt Solution(14015-069, Life Technologies, Gaithersburg, Md.) with additions of 10mM HEPES pH 7.5, 5 mM MgCl₂, 1 mM glutamine and 1 mg/ml bovine serumalbumin. Cells were counted and diluted to 1 to 5×10⁶/ml. Thephosphodiesterase inhibitor 3-isobutyl-1-methylxanthine was added tocells to 0.6 mM.

Test compounds were diluted in dimethylsulfoxide (DMSO) (10⁻⁵ to 10⁻¹⁰M) and 0.1 volume of compound solution was added to 0.9 volumes of cellsuspension; the final DMSO concentration was 1%. After room temperatureincubation for 45 min., cells were lysed by incubation at 100° C. for 5min. to release accumulated cAMP.

cAMP was measured in an aliquot of the cell lysate with the Amersham(Arlington Heights, Ill.) cAMP detection assay (RPA556). The amount ofcAMP production which resulted from an unknown compound was compared tothat amount of cAMP produced in response to alpha-MSH which was definedas a 100% agonist. The EC₅₀ is defined as the compound concentrationwhich results in half maximal stimulation, when compared to its ownmaximal level of stimulation.

Antagonist assay: Antagonist activity was defined as the ability of acompound to block cAMP production in response to alpha-MSH. Solution oftest compounds and suspension of receptor containing cells were preparedand mixed as described above; the mixture was incubated for 15 min., andan EC50 dose (approximately 10 nM alpha-MSH) was added to the cells. Theassay was terminated at 45 min. and cAMP quantitated as above. Percentinhibition was determined by comparing the amount of cAMP produced inthe presence to that produced in the absence of test compound.

C. In Vivo Food Intake Models

1) Overnight food intake. Sprague Dawley rats are injectedintracerebroventricularly with a test compound in 400 nL of 50%propylene glycol/artificial cerebrospinal fluid one hour prior to onsetof dark cycle (12 hours). Food intake is determined using a computerizedsystem in which each rat's food is placed on a computer monitoredbalance. Cumulative food intake for 16 hours post compoundadministration is measured.

2) Food intake in diet induced obese mice. Male C57/B16J mice maintainedon a high fat diet (60% fat calories) for 6.5 months from 4 weeks of ageare are dosed intraperitoneally with test compound. Food intake and bodyweight are measured over an eight day period. Biochemical parametersrelating to obesity, including leptin, insulin, triglyceride, free fattyacid, cholesterol and serum glucose levels are determined.

D. Rat Ex Copula Assay

Sexually mature male Caesarian Derived Sprague Dawley (CD) rats (over 60days old) are used with the suspensory ligament surgically removed toprevent retraction of the penis back into the penile sheath during theex copula evaluations. Animals receive food and water ad lib and arekept on a normal light/dark cycle. Studies are conducted during thelight cycle.

1) Conditioning to Supine Restraint for Ex Copula Reflex Tests. Thisconditioning takes ˜4 days. Day 1, the animals are placed in a darkenedrestrainer and left for 15–30 minutes. Day 2, the animals are restrainedin a supine position in the restrainer for 15–30 minutes. Day 3, theanimals are restrained in the supine position with the penile sheathretracted for 15–30 minutes. Day 4, the animals are restrained in thesupine position with the penile sheath retracted until penile responsesare observed. Some animals require additional days of conditioningbefore they are completely acclimated to the procedures; non-respondersare removed from further evaluation. After any handling or evaluationanimals are given a treat to ensure positive reinforcement.

2) Ex Copula Reflex Tests. Rats are gently restrained in a supineposition with their anterior torso placed inside a cylinder of adequatesize to allow for normal head and paw grooming. For a 400–500 gram rat,the diameter of the cylinder is approximately 8 cm. The lower torso andhind limbs are restrained with a non-adhesive material (vetrap). Anadditional piece of vetrap with a hole in it, through which the glanspenis will be passed, is fastened over the animal to maintain thepreputial sheath in a retracted position. Penile responses will beobserved, typically termed ex copula genital reflex tests. Typically, aseries of penile erections will occur spontaneously within a few minutesafter sheath retraction. The types of normal reflexogenic erectileresponses include elongation, engorgement, cup and flip. An elongationis classified as an extension of the penile body. Engorgement is adilation of the glans penis. A cup is defined as an intense erectionwhere the distal margin of the glans penis momentarily flares open toform a cup. A flip is a dorsiflexion of the penile body.

Baseline and or vehicle evaluations are conducted to determine how andif an animal will respond. Some animals have a long duration until thefirst response while others are non-responders altogether. During thisbaseline evaluation latency to first response, number and type ofresponses are recorded. The testing time frame is 15 minutes after thefirst response.

After a minimum of 1 day between evaluations, these same animals areadministered the test compound at 20 mg/kg and evaluated for penilereflexes. All evaluations are videotaped and scored later. Data arecollected and analyzed using paired 2 tailed t-tests to comparedbaseline and/or vehicle evaluations to drug treated evaluations forindividual animals. Groups of a minimum of 4 animals are utilized toreduce variability.

Positive reference controls are included in each study to assure thevalidity of the study. Animals can be dosed by a number of routes ofadministration depending on the nature of the study to be performed. Theroutes of administration includes intravenous (IV), intraperitoneal(IP), subcutaneous (SC) and intracerebral ventricular (ICV).

E. Models of Female Sexual Dysfunction

Rodent assays relevant to female sexual receptivity include thebehavioral model of lordosis and direct observations of copulatoryactivity. There is also a urethrogenital reflex model in anesthetizedspinally transected rats for measuring orgasm in both male and femalerats. These and other established animal models of female sexualdysfunction are described in McKenna K E et al, A Model For The Study ofSexual Function In Anesthetized Male And Female Rats, Am. J. Physiol.(Regulatory Integrative Comp. Physiol 30): R1276–R1285, 1991; McKenna KE et al, Modulation By Peripheral Serotonin of The Threshold For SexualReflexes In Female Rats, Pharm. Bioch. Behav., 40:151–156, 1991; andTakahashi L K et al, Dual Estradiol Action In The Diencephalon And TheRegulation Of Sociosexual Behavior In Female Golden Hamsters, BrainRes., 359:194–207, 1985.

Representative compounds of the present invention were tested and foundto bind to the melanocortin-4 receptor. These compounds were generallyfound to have IC₅₀ values less than 2 μM. Representative compounds ofthe present invention were also tested in the functional assay and foundgenerally to activate the melanocortin-4 receptor with EC₅₀ values lessthan 1 μM.

EXAMPLES OF A PHARMACEUTICAL COMPOSITION

As a specific embodiment of an oral composition of a composition of thepresent invention, 5 mg of Example 2 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

As another specific embodiment of an oral composition of a compound ofthe present invention, 2.5 mg of Example 2 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein m is 1 or 2; eachn is independently 0, 1, or 2; each p is independently 0, 1 or 2; q is 1or 2; R¹ is selected from the group consisting of hydrogen, C₁₋₈ alkyl,(CHR⁷)_(n)—C₃₋₆ cycloalkyl, (CHR⁷)_(q)—O(CHR⁷)aryl, (CHR⁷)_(n)-aryl, and(CHR⁷)_(n)-heteroaryl; wherein aryl and heteroaryl are unsubstituted orsubstituted with one to three groups independently selected from R⁶; andalkyl and cycloalkyl are unsubstituted or substituted with one to threegroups independently selected from R⁶ and oxo; R² is selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, (CH₂)_(n)C₃₋₆ cycloalkyl, and(CH₂)_(n)-aryl; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, (CH₂)_(n)C₃₋₆ cycloalkyl,(CH₂)_(n)-aryl, hydroxy, halogen, and amino; R⁵ is selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)C₃₋₆cycloalkyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, COC(R⁷)₂NH₂,COR⁷, (CH₂)_(n)OR⁷, (CH₂)_(n)CO₂R⁷, (CH₂)_(n)CONR⁷R⁷, CH₂C≡CH, CO₂R⁷,CH₂CHF₂, CONR⁷R⁷, and SO₂R⁷; wherein aryl and heteroaryl areunsubstituted or substituted with one to three groups independentlyselected from R⁶; and alkyl, cycloalkyl, and heterocyclyl areunsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; each R⁶ is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl,(CH₂)_(n)C₃₋₇ cycloalkyl, halogen, OR⁷, (CH₂)_(n)N(R⁷)₂, (CH₂)_(n)C≡N,(CH₂)_(n)CO₂R⁷, NO₂, (CH₂)_(n)NR⁷SO₂R⁷, (CH₂)_(n)SO₂N(R⁷)₂,(CH₂)_(n)S(O)_(p)R⁷, (CH₂)_(n)NR⁷C(O)N(R⁷)₂, (CH₂)_(n)C(O)N(R⁷)₂,(CH₂)_(n)NR⁷C(O)R⁷, (CH₂)_(n)NR⁷CO₂R⁷, O(CH₂)_(n)C(O)N(R⁷)₂, CF₃,CH₂CF₃, OCF₃, and OCH₂CF₃; wherein phenyl, naphthyl, heteroaryl,cycloalkyl, and heterocyclyl are unsubstituted or substituted with oneto three substituents independently selected from halogen, hydroxy, C₁₋₄alkyl, trifluoromethyl, and C₁₋₄ alkoxy; and wherein any methylene (CH₂)carbon atom in R⁶ is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkyl; or twosubstituents when on the same methylene (CH₂) carbon atom are takentogether with the carbon atom to which they are attached to form acyclopropyl group; each R⁷ is independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, (CH₂)_(n)-phenyl,(CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl, and (CH₂)_(n)C₃₋₇ cycloalkyl;wherein phenyl, naphthyl, and heteroaryl are unsubstituted orsubstituted with one to three groups independently selected from R⁶;alkyl and cycloalkyl are unsubstituted or substituted with one to threegroups independently selected from R⁶ and oxo; and wherein any methylene(CH₂) carbon atom in R⁷ is unsubstituted or substituted with one to twogroups independently selected from halogen, hydroxy, and C₁₋₄ alkyl; ortwo R⁷ groups together with the atom to which they are attached form a5- to 8-membered mono- or bicyclic ring system optionally containing anadditional heteroatom selected from O, S, and NC₁₋₄ alkyl; each R⁸ isindependently selected from the group consisting of hydrogen,(CH₂)_(n)C₁₋₇ alkyl, (CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)-heterocyclyl, and (CH₂)_(n)C₃₋₇ cycloalkyl; wherein aryl andheteroaryl are unsubstituted or substituted with one to three groupsindependently selected from R⁶; and alkyl, cycloalkyl, heterocyclyl, and(CH₂)_(n) are unsubstituted or substituted with one to three groupsindependently selected from R⁶ and oxo; or two substituents when on thesame methylene (CH₂) carbon atom are taken together with the carbon atomto which they are attached to form a cyclopropyl group; or two R⁸ groupstogether with the atoms to which they are attached form a 5- to8-membered mono- or bi-cyclic ring system optionally containing anadditional heteroatom selected from O, S, NR⁷, NBoc, and NCbz; X isselected from the group consisting of C₁₋₈ alkyl, (CH₂)_(n)C₃₋₈cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl, (CH₂)_(n)-heteroaryl,(CH₂)_(n)heterocyclyl, (CH₂)_(n)C≡N, (CH₂)_(n)CON(R⁸R⁸), (CH₂)_(n)CO₂R⁸,(CH₂)_(n)COR⁸, (CH₂)_(n)NR⁸C(O)R⁸, (CH₂)_(n)NR⁸CO₂R⁸,(CH₂)_(n)NR⁸C(O)N(R⁸)₂, (CH₂)_(n)NR⁸SO₂R⁸, (CH₂)_(n)S(O)_(p)R⁸,(CH₂)_(n)SO₂N(R⁸)(R⁸), (CH₂)_(n)OR⁸, (CH₂)_(n)OC(O)R⁸,(CH₂)_(n)OC(O)OR⁸, (CH₂)_(n)OC(O)N(R⁸)₂, (CH₂)_(n)N(R⁸)(R⁸), and(CH₂)_(n)NR⁸SO₂N(R⁸)(R⁸); wherein phenyl, naphthyl, and heteroaryl areunsubstituted or substituted with one to three groups independentlyselected from R⁶; alkyl, cycloalkyl, and heterocyclyl are unsubstitutedor substituted with one to three groups independently selected from R⁶and oxo; and wherein any methylene (CH₂) carbon atom in X isunsubstituted or substituted with one to two groups independentlyselected from halogen, hydroxy, and C₁₋₄ alkyl; and Y is selected fromthe group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₆ alkenyl,(CH₂)_(n)C₃₋₈ cycloalkyl, (CH₂)_(n)-phenyl, (CH₂)_(n)-naphthyl,(CH₂)_(n)-heteroaryl, and (CH₂)_(n)-heterocyclyl; wherein phenyl,naphthyl, and heteroaryl are unsubstituted or substituted with one tothree groups independently selected from R⁶; alkyl, cycloalkyl, andheterocyclyl are optionally substituted with one to three groupsindependently selected from R⁶ and oxo; and wherein any methylene (CH₂)carbon atom in Y is unsubstituted or substituted with one to two groupsindependently selected from halogen, hydroxy, and C₁₋₄ alkyl.
 2. Thecompound of claim 1 wherein R¹ is CHR⁷-aryl, CHR⁷OCHR⁷-aryl, orCHR⁷-heteroaryl wherein aryl and heteroaryl are unsubstituted orsubstituted with one to two groups independently selected from R⁶. 3.The compound of claim 2 wherein R¹ is benzyl optionally substituted withone or two groups independently selected from halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, CN, CF₃, and OCF₃.
 4. The compound of claim 3 wherein R¹ is4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl; 3,5-difluorobenzyl;2-cyano-4-fluorobenzyl; or 4-methoxybenzyl.
 5. The compound of claim 1wherein R² is hydrogen or methyl.
 6. The compound of claim 1 wherein R⁵is selected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl,(CH₂)_(n)C₃₋₆ cycloalkyl, (CH₂)_(n)CO₂R⁷, (CH₂)_(n)CONR⁷R⁷,(CH₂)_(n)OR⁷, COC(R⁷)NH₂, CH₂C≡CH, and CH₂CHF₂; wherein aryl andheteroaryl are unsubstituted or substituted with one to three groupsindependently selected from R⁶; and alkyl, cycloalkyl, and heterocyclylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo.
 7. The compound of claim 6 wherein X isselected from the group consisting of C₁₋₆ alkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl, (CH₂)_(n)C(O)N(R⁸)(R⁸),(CH₂)_(n)CO₂R⁸, (CH₂)_(n)OR⁸, (CH₂)_(n)S(O)₀₋₂R⁸, (CH₂)_(n)NHC(O)R⁸,(CH₂)_(n)OC(O)NR⁸R⁸, and (CH₂)_(n)NR⁸SO₂R⁸; wherein aryl and heteroarylare optionally substituted with one to three groups independentlyselected from R⁶; heterocyclyl is optionally substituted with one tothree groups independently selected from R⁶ and oxo; the (CH₂)_(n) groupis optionally substituted with one to three groups independentlyselected from R⁷, halogen, S(O)₀₋₂R⁷, N(R⁷)₂, and OR⁷; and each R⁸ isindependently selected from H, C₁₋₈ alkyl, and C₃₋₆ cycloalkyl, whereinalkyl and cycloalkyl are optionally substituted with one to three groupsindependently selected from R⁶ and oxo; or two R⁸ groups together withthe atoms to which they are attached form a 5- to 8-membered mono- orbi-cyclic ring system optionally containing an additional heteroatomselected from O, S, NR⁷, NBoc, and NCbz.
 8. The compound of claim 7wherein X is selected from the group consisting of C₁₋₆ alkyl,(CH₂)₀₋₁-heteroaryl, CH₂-heterocyclyl, CO₂R⁸, CH₂OR⁸, CH₂S(O)₀₋₂R⁸,NHC(O)R⁸, CH₂NR⁸SO₂R⁸, CH₂OC(O)NR⁸R⁸, CH₂NR⁸SO₂R⁸, and C(O)N(R⁸)(R⁸);wherein heteroaryl is optionally substituted with one to three groupsindependently selected from R⁶; heterocyclyl is optionally substitutedwith one to three groups independently selected from R⁶ and oxo; andeach R⁸ is independently selected from H, C₁₋₈ alkyl, and C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted withone to three groups independently selected from R⁶ and oxo; or two R⁸groups together with the atoms to which they are attached form a 5- to8-membered mono- or bi-cyclic ring system optionally containing anadditional heteroatom selected from O, S, NR⁷, NBoc, and NCbz.
 9. Thecompound of claim 1 wherein Y is selected from the group consisting ofC₁₋₈ alkyl, (CH₂)_(n)C₃₋₇ cycloalkyl, (CH₂)_(n)-aryl,(CH₂)_(n)-heterocyclyl, and (CH₂)_(n)-heteroaryl; wherein aryl andheteroaryl are optionally substituted with one to three groupsindependently selected from R⁶; and (CH₂)_(n), alkyl, cycloalkyl, andheterocyclyl are optionally substituted with one to three groupsindependently selected from R⁶ and oxo.
 10. The compound of claim 9wherein Y is cyclohexyl, cycloheptyl, cyclopentyl, or C₁₋₆ alkyl;wherein alkyl and cycloalkyl groups are unsubstituted or substitutedwith one to three groups independently selected from R⁶ and oxo.
 11. Thecompound of claim 10 wherein Y is cyclohexyl or C₁₋₆ alkyl; wherein thecyclohexyl and alkyl groups are unsubstituted or substituted with one tothree groups independently selected from R⁶ and oxo.
 12. The compound ofclaim 1 of formula II:

wherein m is 1 or 2; each n is independently 0, 1, or 2; R² is hydrogenor methyl; R³ is hydrogen, fluoro, or hydroxy; each R⁶ is independentlyselected from the group consisting of hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, trifluoromethyl, and trifluoromethoxy; R⁵ isselected from the group consisting of hydrogen, C₁₋₈ alkyl,(CH₂)_(n)-aryl, (CH₂)_(n)-heteroaryl, (CH₂)_(n)-heterocyclyl,(CH₂)_(n)C₃₋₆ cycloalkyl, (CH₂)_(n)CO₂R⁷, (CH₂)_(n)CONR⁷R⁷,(CH₂)_(n)OR⁷, COC(R⁷)NH₂, CH₂C≡CH, and CH₂CHF₂; wherein aryl andheteroaryl are unsubstituted or substituted with one to three groupsindependently selected from R⁶; and alkyl, cycloalkyl, and heterocyclylare unsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; Y is selected from the group consisting ofC₅₋₇ cycloalkyl and C₁₋₆ alkyl; wherein alkyl and cycloalkyl areunsubstituted or substituted with one to three groups independentlyselected from R⁶ and oxo; and X is selected from the group consisting of

—NHC(O)tBu; —C(O)NHCH(Et)₂; —C(O)NHCH₂tBu;

 —CH₂SCH(CH₃)₂; —CH₂S(O)CH(CH₃)₂; —CH₂S(O)₂CH(CH₃)₂;—C(O)NHCH₂CH₂N(CH₃)₂; C(O)CH(CH₃)₂; —CH₂NHCOtBu; —CH₂OC(O)NMe₂;—CH₂C(O)NEt₂; —CH₂OC(Me)₂CO₂H; —C(O)NHC(Me)₂CO₂Me; —C(O)NHC(Me)₂CO₂H;—CH₂N(CH₃)COtBu; —CH₂N(iPr)COMe; —CH₂N(iPr)SO₂Me; C(O)NHC(Me)₂CH₂OMe;C(O)NHC(Me)₂CH₂OH; —CH₂CH₂C(Me)₂OH;


13. The compound of claim 12 wherein the carbon atom marked with an *has the R configuration.
 14. The compound of claim 13 selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition which comprises a therapeutically effective amount of acompound of claim 1 and a pharmaceutically acceptable carrier.
 16. Amethod for the treatment of obesity in a subject in need thereof whichcomprises administering to the subject a therapeutically effectiveamount of a compound according to claim
 1. 17. A method for thetreatment of diabetes mellitus in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound according to claim
 1. 18. A method for the treatment of male orfemale sexual dysfunction in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound according to claim
 1. 19. A method for the treatment oferectile dysfunction in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound according to claim 1.